Substituted azetidinones as anti-inflammatory and antidegenerative agents

ABSTRACT

New substituted azetidinones of the general Formula (I) which have been found to be potent elastase inhibitors and thereby useful anti-inflammatory and antidegenerative agents are described. ##STR1## wherein R 4  is (a) ##STR2## or  (b) ##STR3##  where R x  is carboxy C 1-6  alkyl, benzyloxycarbonylC 1-3  alkyl, or t-butoxycarbonylC 1-3  alkyl, 
     wherein 
     Q is a covalent bond or ##STR4## wherein R 5  and R 6  are each individually C 1-3  alkyl or hydrogen, 
     Y is ##STR5## or a covalent bond.

This is a continuation of application Ser. No. 07/991,838 filed on Dec. 17, 1992, abandoned.

BACKGROUND OF THE INVENTION

We have found that a group of new substituted azetidinones are potent elastase inhibitors and therefore are useful anti-inflammatory and antidegenerative agents.

Proteases from granulocytes and macrophages have been reported to be responsible for the chronic tissue destruction mechanisms associated with inflammation, including rheumatoid arthritis and emphysema. Accordingly, specific and selective inhibitors of these proteases are candidates for potent anti-inflammatory agents useful in the treatment of inflammatory conditions resulting in connective tissue destruction, e.g. rheumatoid arthritis, emphysema, bronchial inflammation, chronic bronchitis, glomerulonephritis, osteoarthritis, spondylitis, lupus, psoriasis, atherosclerosis, sepsis, septicemia, shock, myocardial infarction, reperfusion injury, periodontitis, cystic fibrosis and acute respiratory distress syndrome.

The role of proteases from granulocytes, leukocytes or macrophages are related to a rapid series of events which occurs during the progression of an inflammatory condition:

(1) There is a rapid production of prostaglandins (PG) and related compounds synthesized from arachidonic acid. This PG synthesis has been shown to be inhibited by aspirin-related nonsteroidal anti-inflammatory agents including indomethacin and phenylbutazone. There is some evidence that protease inhibitors prevent PG production;

(2) There is also a change in vascular permeability which causes a leakage of fluid into the inflamed site and the resulting edema is generally used as a marker for measuring the degree of inflammation. This process has been found to be induced by the proteolytic or peptide cleaving activity of proteases, especially those contained in the granulocyte, and thereby can be inhibited by various synthetic protease inhibitors, for example, N-acyl benzisothiazolones and the respective 1,1-dioxides. Morris Zimmerman et al., J. Biol. Chem., 255, 9848 (1980); and

(3) There is an appearance and/or presence of lymphoid cells, especially macrophages and polymorphonuclear leukocytes (PMN). It has been known that a variety of proteases are released from the macrophages and PMN, further indicating that the proteases do play an important role in inflammation.

In general, proteases are an important family of enzymes within the peptide bond cleaving enzymes whose members are essential to a variety of normal biological activities, such as digestion, formation and dissolution of blood clots, the formation of active forms of hormones, the immune reaction to foreign cells and organisms, etc., and in pathological conditions such as the degradation of structural proteins at the articular cartilage/pannus junction in rheumatoid arthritis etc.

Elastase is one of the proteases. It is an enzyme capable of hydrolyzing the connective tissue component elastin, a property not contained by the bulk of the proteases present in mammals. It acts on a protein's nonterminal bonds which are adjacent to an aliphatic amino acid. Neutrophil elastase is of particular interest because it has the broadest spectrum of activity against natural connective tissue substrates. In particular, the elastase of the granulocyte is important because, as described above, granulocytes participate in acute inflammation and in acute exacerbation of chronic forms of inflammation which characterize many clinically important inflammatory diseases.

Proteases may be inactivated by inhibitors which block the active site of the enzyme by binding tightly thereto. Naturally occurring protease inhibitors form part of the control or defense mechanisms that are crucial to the well-being of an organism. Without these control mechanisms, the proteases would destroy any protein within reach. The naturally occurring enzyme inhibitors have been shown to have appropriate configurations which allow them to bind tightly to the enzyme. This configuration is part of the reason that inhibitors bind to the enzyme so tightly (see Stroud, "A Family of Protein-Cutting Proteins" Sci. Am. July 1974, pp. 74-88). For example, one of the natural inhibitors, α₁ -Antitrypsin, is a glycoprotein contained in human serum that has a wide inhibitory spectrum covering, among other enzymes, elastase both from the pancreas and the PMN. This inhibitor is hydrolyzed by the proteases to form a stable acyl enzyme in which the active site is no longer available. Marked reduction in serum α₁ -antitrypsin, either genetic or due to oxidants, has been associated with pulmonary emphysema which is a disease characterized by a progressive loss of lung elasticity and resulting respiratory difficulty. It has been reported that this loss of lung elasticity is caused by the progressive, uncontrolled proteolysis or destruction of the structure of lung tissue by proteases such as elastase released from leukocytes. J. C. Powers, TIBS, 211 (1976).

Rheumatoid arthritis is characterized by a progressive destruction of articular cartilage both on the free surface bordering the joint space and at the erosion front built up by synovial tissue toward the cartilage. This destruction process, in turn, is attributed to the protein-cutting enzyme elastase which is a neutral protease present in human granulocytes. This conclusion has been supported by the following observations:

(1) Recent histochemical investigations showed the accumulation of granulocytes at the cartilage/pannus junction in rheumatoid arthritis; and

(2) a recent investigation of mechanical behavior of cartilage in response to attack by purified elastase demonstrated the direct participation of granulocyte enzymes, especially elastase, in rheumatoid cartilage destruction. H. Menninger etal., in Biological Functions of Proteinases, H. Holzer and H. Tschesche, eds. Springer-Verlag, Berlin, Heidelberg, New York, pp. 196-206, 1979.

In a second aspect this invention concerns the use of novel azetidinones in the treatment of certain cancers including nonlymphoblastic leukemias, acute myelogenous leukemia (FAB M1 and FAB M2), acute promyelocytic leukemia (FAB M3), acute myelomonocytic leukemia (FAB M4), acute monocytic leukemia (FAB M5), erythroleukemia, chronic myelogenous leukemia, chronic myelomonocytic leukemia, chronic monocytic leukemia and conditions associated with leukemia involving activity of PMN neutral proteases e.g. disseminated intravascular coagulation. We have found that the substituted azetidinones disclosed herein are inhibitors of proteinase 3 (PR-3), also known as myeloblastin.

See C. Labbaye, et al., Proc. Natl. Acad. Sci. USA, vol. 88, 9253-9256, (1991), Wegner autoantigen and myeloblastin are encoded by a single mRNA; D. Campanelli, et al., J. Exp. Med., vol. 172, 1709-1714, (1990), Cloning of cDNA for proteinase 3: A serine protease, antibiotic, and autoantigen from human neutrophils; and Bories, st. al., Cell vol. 59, 959-968, (1989) Down-regulation of a serine protease, myeloblastin, causes growth arrest and differentiation of promyelocytic leukemia cells.

Recently, down regulation of PR-3 has been implicated in the proliferation and maintenance of a differentiated state of certain leukemia cells. In particular, Bories, et. al., have shown that expression of this enzyme, hereinafter designated proteinase 3/myeloblastin, can be inhibited by treatment of HL-60 human leukemia cells with an antisense oligodeoxynucleotide and that such treatment induces differentiation and inhibits proliferation of these cells. Moreover, we have now demonstrated that the treatment of the HL-60 cell human leukemia cell line, among others, with the compounds of the instant invention, likewise results in the inhibition of proliferation and induction of differentiation in such cells.

Accordingly, we believe that treatment of leukemia such as nonlymphoblastic leukemias, acute myelogenous leukemia (FAB M1 and FAB M2), acute promyelocytic leukemia (FAB M3), acute myelomonocytic leukemia (FAB M4), acute monocytic leukemia (FAB M5), erythroleukemia, chronic myelogenous leukemia, chronic myelomonocytic leukemia, chronic monocytic leukemia and conditions associated with leukemia involving activity of PMN neutral proteases e.g. disseminated intravascular coagulation, comprising: administration of a therapeutically effective amount of compound of Formula I will result in remission of the disease state. Administration may be either oral or parenteral.

BRIEF DESCRIPTION OF THE INVENTION

The instantly claimed invention is directed to specifically substituted azetidinones of Formula I ##STR6##

These substituted azetidinones have been found to be useful anti-inflammatory and antidegenerative agents. This invention is also directed to pharmaceutical compositions and methods of using these specifically substituted azetidinones.

These compounds will also be useful in the treatment of certain leukemias and leukemia related conditions.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to potent-elastase inhibitors of Formula (I), ##STR7## which are useful in the prevention, control and treatment of inflammatory and degenerative conditions especially arthritis and emphysema.

More particularly, the instant invention is directed to the compounds of the Formula (I) ##STR8## and pharmaceutically acceptable salts thereof wherein: R is C₁₋₆ alkyl;

R¹ is C₁₋₆ alkyl or C₁₋₆ alkoxy-C₁₋₆ alkyl;

M is

(1) hydrogen,

(2) C₁₋₆ alkyl,

(3) hydroxy C₁₋₆ alkyl,

(4) halo C₁₋₆ alkyl,

(5) C₂₋₆ alkenyl, or

(6) C₁₋₆ alkoxy-C₁₋₆ alkyl;

Ra and Rb are each individually

(1) hydrogen,

(2) C₁₋₆ alkyl,

(3) halo,

(4) carboxy,

(5) C₁₋₆ alkoxy,

(6) phenyl,

(7) C₁₋₆ alkylcarbonyl,

(8) di-(C₁₋₆ alkyl)amino;

(9) hydroxy;

R² and R³ are each independently

(1) hydrogen,

(2) C₁₋₆ alkyl,

(3) halo,

(4) carboxy,

(5) C₁₋₆ alkoxy,

(6) phenyl,

(7) C₁₋₆ alkylcarbonyl,

(8) aminoC₂₋₃ alkyloxy carbonyl wherein the amino is optionally mono or di substituted with C₁₋₆ alkyl,

(9) aminoC₂₋₃ alkylamino carbonyl wherein the amino is optionally mono or di substituted with C₁₋₆ alkyl,

(10) hydroxy,

(11) aminocarbonyl wherein the amino is optionally mono or di substituted with C₁₋₆ alkyl,

(12) hydroxymethyl,

(13) aminocarbonyloxy C₁₋₃ alkyloxy wherein the amino is optionally mono or di substituted with C₁₋₆ alkyl,

(14) cyano,

(15) morpholinocarbonylphenyl,

(16) amino wherein the amino is optionally mono or di substituted with C₁₋₆ alkyl, with the proviso that R² and R³ may be joined together to form a methylenedioxy group or a furan ring,

(17) morpholinocarbonyl;

R₄ is (a) ##STR9## or (b) ##STR10## where R_(x) is carboxy C₁₋₆ alkyl, benzyloxycarbonylC₁₋₃ alkyl, or t-butoxycarbonylC₁₋₃ alkyl,

wherein

Q is a covalent bond or ##STR11## wherein R₅ and R₆ are each individually C₁₋₃ alkyl or,hydrogen,

Y is ##STR12## or a covalent bond; R₁₂ is hydrogen or C₁₋₃ alkyl;

R₇ and R₈ are each individually

(a) hydrogen,

(b) C₁₋₆ alkyl,

(c) C₁₋₆ alkyloxy C₂₋₃ alkyl,

(d) hydroxy C₂₋₆ alkyl,

(e) polyhydroxyC₂₋₆ alkyl,

(f) carboxamido C₁₋₆ alkyl,

(g) polyacyloxyC₂₋₆ alkyl

(h) C₁₋₆ alkanoyl,

(i) substituted phenyl or phenyl C₁₋₆ alkyl, wherein the substitutent is X₁ as defined immediately below,

(j) C₂₋₆ alkenyl,

(k) C₆₋₁₀ cycloalkenyl,

(l) heteroaryl C₁₋₆ alkyl wherein the hetero aryl includes pyridinyl, imidazolyl, triazolyl, benzylimidazolyl, and furyl,

(m) carboxy C₁₋₆ alkyl,

(n) carbo C₁₋₆ alkoxy C₁₋₃ alkyl,

(o) phenylsulfonyl,

(p) C₁₋₆ alkylsulfonyl,

(q) benzyloxy,

(r) morpholinyl C₁₋₃ alkylsulfonyl,

(s) tetrahydropyranyl,

(t) aminoC₁₋₃ alkylsulfonyl wherein the amino is optionally mono or di substituted with C₁₋₆ alkyl,

(u) aminocarbonyl wherein the amino is optionally mono or di substituted with C₁₋₆ alkyl,

(v) aminocarbonyloxyC₂₋₆ alkyl wherein the amino is optionally mono or di substituted with C₁₋₆ alkyl,

(w) azabicyclo of 7 to 12 atoms,

(x) di C₁₋₃ alkylamino C₂₋₆ alkyl wherein the amino is optionally mono or di substituted with C₁₋₆ alkyl,

(y) bicycloalkyl of 7 to 12 atoms,

(z) C₃₋₁₀ cycloalkyl optionally substituted with C₁₋₆ alkyl,

(aa) pyrazolidinyl,

(bb) substituted piperidinyl or prrrolidinyl wherein the substitutent is hydrogen, C₁₋₃ alkyl, hydroxyC₁₋₃ alkylbenzyl, carboxamido or amino wherein the amino is optionally mono or di substituted with C₁₋₆ alkyl,

(cc) substituted pyrrolidinyl wherein the substitutent is carboxamido or amino wherein the amino is optionally mono or di substituted with C₁₋₆ alkyl,

(dd) pyrimidinyl,

(ee) N-cyano-N'-phenylamidino,

(ff) phosphonoC₁₋₆ alkyl, or

(gg) α-C₁₋₃ alkyl benzyl or mono or di substituted benzyl or mono or di substituted pyridylmethyl, wherein the substitutents are X₁ and X₂,

wherein

X₁ is

(1) hydrogen,

(2) halo,

(3) C₁₋₆ alkyl,

(4) halo-C₁₋₆ alkyl,

(5) C₂₋₆ alkenyl,

(6) hydroxy-C₁₋₆ alkyl,

(7) C₁₋₆ alkylcarbonyl,

(8) C₁₋₆ alkylcarbonylamino;

(9) CN,

(10) CF₃,

(11) CH₃ O,

(12) amino wherein the amino is optionally mono or di substituted with C₁₋₆ alkyl;

(13) carboxy, or

(14) phenylsulfonylaminocarbonyl; X₂ is hydrogen, halo or C₁₋₆ alkyl;

n is 1, 2, 3, 4 or 5;

R₉ is selected from hydrogen, C₁₋₄ alkyl, and C₁₋₃ alkoxyC₁₋₃ alkyl; or phenyl, phenyl C₁₋₃ alkyl, pyridyl, and pyridyl C₁₋₃ alkyl;

R₁₀ and R₁₁ are each independently selected from hydrogen, C₁₋₄ alkyl, and C₁₋₃ alkoxy C₁₋₃ alkyl, or aryl as defined above, or are together O═; or

wherein

R₇ and R₈ are joined together to form mono or di substituted ring of 4, 5, 6, or 7 atoms or 7 to 12 atoms such as

(1) piperidinyl or homopiperdinyl,

(2) piperazinyl,

(3) morpholinyl, thiomorpholinyl or 1,1-dioxo-4-thiomorpholinyl,

(4) pyrroylidinyl,

(5) pyrryl,

(6) imidazolyl,

(7) triazolyl,

(8) saturated azabicyclo of 7 to 12 atoms

(9) azaspiro having 3 to 9 carbon atoms, said ring being saturated,

(10) tetrazolyl,

(11) pyrazolidinyl,

(12) dihydodimethoxyisoquinolyl,

(13) azetidinyl, or

(14) diazabicyclo ring of 7-12 atoms,

wherein the substituents are each selected from the group consisting of hydrogen and C₁₋₃ alkyl, benzyloxycarbonyl, carboxy, phenyl C₁₋₃ alkyl amino carbonyl, pyrrolidinylmethyl, hydroxy C₁₋₃ alkyl, C₁₋₆ alkyloxy, C₁₋₄ alkyloxy carbonyl, aminocarbonyl wherein the amino is optionally mono or di substituted with C₁₋₆ alkyl, and oxo; or --N(R7)R8 may be an amino acid residue including natural amino acids such as lysine; or R₈ and R₉ are joined together to form a mono or di substituted saturated monocyclic ring of 6 to 7 atoms and having two hetero atoms which are the nitrogens to which R₈ and R₉ are attached; said rings to include piperazinyl and homopiperazinyl; or R₉ and R₁₀ are joined together to form a mono or di substituted monocyclic saturated ring of 5 to 7 atoms and having one hetero atom which is the nitrogen to which R₉ is attached; or

wherein R₉ and R₁₂ are joined together to form a mono or di substituted saturated monocyclic ring of 5, 6, or 7 atoms, said ring having one hetero atom which is the nitrogen to which R₉ is attached; or wherein R₁₀ and R₁₂ are joined together to form a mono or di substituted saturated monocyclic ring of 5, 6, or 7 carbon atoms; or

wherein R₈ and R₁₁ are joined together to form a mono or di substituted saturated monocyclic ring of 5, 6, or 7 atoms, said ring having one hetero atom which is the nitrogen to which R₈ is attached; and the substituents are independently selected-from Hydrogen and C1-3alkyl.

As appreciated by those of Skill in the art the term "alkyl" such as in C₁₋₆ alkyl, includes, methyl, ethyl, propyl, butyl, pentyl, and hexyl, and where appropriate, branched chained forms including isopropyl and tert-butyl.

As may also be appreciated by those of skill in the art, the ##STR13## spacer in definition Y, may, in the alternative be placed to the right of CR₁₀ R₁₁.

As may also be appreciated, the group ##STR14## may also be oxidized to the corresponding oxide ##STR15##

In one Class the instant invention is directed to the compounds of the Formula (I) ##STR16## and pharmaceutically acceptable salts thereof wherein: R is C₁₋₆ alkyl;

R¹ is C₁₋₆ alkyl or C₁₋₆ alkoxy-C₁₋₆ alkyl;

M is

(1) hydrogen,

(2) C₁₋₆ alkyl,

(3) hydroxy C₁₋₆ alkyl,

(4) halo C₁₋₆ alkyl,

(5) C₂₋₆ alkenyl, or

(6) C₁₋₆ alkoxy-C₁₋₆ alkyl;

Ra is

(1) hydrogen,

(2) C₁₋₆ alkyl,

(3) halo,

(4) carboxy,

(5) C₁₋₆ alkoxy,

(6) phenyl,

(7) C₁₋₆ alkylcarbonyl,

(8) amino wherein the amino is optionally mono or di substituted with C₁₋₆ alkyl;

Rb is hydrogen, or C₁₋₆ alkyl,

R² and R³ are each independently

(1) hydrogen,

(2) C₁₋₆ alkyl,

(3) halo,

(4) carboxy,

(5) C₁₋₆ alkoxy,

(6) phenyl,

(7) C₁₋₆ alkylcarbonyl,

(8) amino wherein the amino is optionally mono or di substituted with C₁₋₆ alkyl, or with the proviso that R² and R³ may be joined together to form a methylenedioxy group or a furan ring;

R₄ is (a) ##STR17## or (b) ##STR18## where R_(x) is carboxyC₁₋₆ alkyl, benzyloxycarbonylC₁₋₃ alkyl, or t-butoxycarbonylC₁₋₃ alkyl,

wherein

Q is a covalent bond or ##STR19## wherein R₅ and R₆ are each individually C₁₋₃ alkyl or hydrogen

Y is ##STR20## or a covalent bond; R₁₂ is hydrogen or C₁₋₃ alkyl;

R₇ and R₈ are each individually

(a) hydrogen,

(b) C₁₋₆ alkyl,

(c) C₁₋₆ alkyloxy C₂₋₃ alkyl,

(d) hydroxy C₂₋₆ alkyl,

(e) carboxamido C₁₋₆ alkyl,

(f) C₁₋₆ alkanoyl,

(g) substituted phenyl or phenyl C₁₋₆ alkyl wherein the substitutents are X₁, and X₂

(h) C₂₋₆ alkenyl,

(i) C₆₋₁₀ cycloalkenyl,

(j) heteroaryl C₁₋₆ alkyl wherein the hetero aryl includes pyridinyl, imidazolyl, triazolyl, benzylimidazolyl, and furyl,

(k) carboxy C₁₋₆ alkyl,

(l) C₁₋₆ alkylsulfonyl,

(m) carboC₁₋₆ alkyloxyC₂₋₃ alkyl,

(n) morpholinyl C₁₋₃ alkylsulfonyl,

(o) aminoC₁₋₃ alkylsulfonyl wherein the amino is optionally mono or di substituted with C₁₋₆ alkyl,

(p) aminocarbonyl wherein the amino is optionally mono or di substituted with C₁₋₆ alkyl,

(q) aminocarbonyloxyC₁₋₆ alkyl wherein the amino,is optionally mono or di substituted with C₁₋₆ alkyl,

(r) di C₁₋₃ alkylamino C₁₋₆ alkyl wherein the amino is optionally mono or di substituted with C₁₋₆ alkyl,

(s) pyrazolidinyl,

(t) substituted piperidinyl as defined above,

(u) substituted pyrrolidinyl as defined above

(v) pyrimidinyl,

(w) benzyloxy,

(x) C₃₋₁₀ cycloalkyl,

(z) α-C₁₋₃ alkyl benzyl or mono or di substituted benzyl or-mono or di substituted pyridylmethyl, wherein the substitutents are X₁ and X₂,

wherein

X₁ is

(1) hydrogen,

(2) halo,

(3) C₁₋₆ alkyl,

(4) halo-C₁₋₆ alkyl,

(5) C₂₋₆ alkenyl,

(6) hydroxy-C₁₋₆ alkyl,

(7) C₁₋₆ alkylcarbonyl,

(8) C₁₋₆ alkylcarbonylamino;

(9) di-C₁₋₃ alkylamino; or

(10) carboxy,

X₂ is hydrogen, halo or C₁₋₆ alkyl;

n is 1, 2, 3, 4 or 5;

R₉ is selected from hydrogen, C₁₋₄ alkyl, and C₁₋₃ alkoxyC₁₋₃ alkyl;

R₁₀ nd R₁₁ are each independently selected from hydrogen, C₁₋₄ alkyl, and C₁₋₃ alkoxy C₁₋₃ alkyl; or

wherein

R₇ and R₈ are joined together to form mono or di substituted ring of 4, 5, 6, or 7 atoms such as

(1) piperidinyl,

(2) piperazinyl,

(3) morpholinyl,

(4) pyrroylidinyl,

(5) pyrryl,

(6) imidazolyl,

(7) triazolyl,

(8) tetrazolyl,

(9) pyrazolidinyl,

(10) azetidinyl,

wherein the substituents are each selected from the group consisting of hydrogen and C₁₋₃ alkyl, benzyloxycarbonyl, carboxy, phenyl C₁₋₃ alkyl amino carbonyl, pyrrolidinyl, methyl, hydroxy C₁₋₃ alkyl, C₁₋₆ alkyloxy, C₁₋₄ alkyloxy carbonyl, and oxo; or R₈ and R₉ are joined together to form a saturated ring of 5 to 7 atoms and having two hetero atoms; or R₉ and R₁₀ are joined together to form a saturated ring of 5 to 7 atoms and having one hetero atom; or wherein R₉ and R₁₂ are joined together to form a ring of 5, 6, or 7 atoms, said ring being saturated; or wherein R₁₀ and R₁₂ are joined together to form a ring of 5, 6, or 7 atoms, said ring being saturated; or

wherein R₈ and R₁₁ are joined together to form a ring of 5, 6, or 7 atoms, said ring being saturated and having one hetero atom.

In one subclass, the invention concerns compounds of Formula I

wherein

R is C₁₋₃ alkyl;

R₁ is C₁₋₃ alkyl;

M is

(a) C₁₋₆ alkyl, or

(b) C₂₋₆ alkenyl;

R² is

(a) hydrogen,

(b) C₁₋₆ alkyl, or C₁₋₆ alkoxy, and

R³ is hydrogen, or

R² and R³ are joined together to form a methylenedioxy group or a furan ring; R₅ and R₆ are each individually hydrogen or C₁₋₃ alkyl;

R₇ and R₈ are each independently selected from

(a) hydrogen,

(b) C₁₋₃ alkyl,

(c) C₁₋₃ alkoxy C₂₋₃ alkyl,

(d) C₃₋₇ cycloalkyl,

(e) hydroxyC₂₋₃ alkyl,

(d) carbo C₁₋₄ alkyloxymethyl,

(g) substituted benzyl wherein the substituents are X₁ and X₂

wherein X₁ is hydrogen and X₂ is

(1) hydrogen,

(2) halo, or

(3) C₁₋₃ alkyl;

n is 1, 2 or 3, and

R₉, R₁₀ and R₁₁ are each independently selected from hydrogen, C₁₋₄ alkyl, and C₁₋₃ alkoxy C₁₋₃ alkyl; or

R₇ and R₈ are joined together to form a substituted ring selected from

(a) piperidinyl,

(b) piperazinyl, and

(c) morpholinyl;

or

R₈ and R₉ are joined together to form a ring of 6 to 7 atoms and having two hetero atoms;

R₉ and R₁₀ are joined together to form a saturated ring of 5 to 7 atoms and having one hetero atom; or wherein R₉ and R₁₂ are joined together to form a ring of 5, 6, or 7 atoms, said ring being saturated; or wherein R₁₀ and R₁₂ are joined together to form a ring of 5, 6, or 7 atoms, said ring being saturated; or

wherein R₈ and R₁₁ are joined together to form a ring of 5, 6, or 7 atoms, said ring being saturated and having one hetero atom.

In a narrower sub-class are the compounds wherein

Q is a covalent bond;

R is methyl or ethyl;

R₁ is methyl or ethyl;

M is

(a) C₁₋₄ alkyl, or

(b) C₂₋₃ alkenyl;

R² is

(a) hydrogen,

(b) C₁₋₃ alkyl, or C₁₋₃ alkoxy, and

R³ is hydrogen, or

R² and R³ are joined together to form a furan or dioxacyclopentane ring;

n is 1 or 2;

R₉ and R₁₀ are each independently selected from

(a) C₁₋₃ alkyl,

(b) C₁₋₃ alkoxy C₁₋₃ alkyl,

(c) hydrogen,

R₇ and R₈ are each independently selected from

(a) C₁₋₃ alkyl,

(b) C₁₋₃ alkoxy C₂₋₃ alkyl,

(c) hydrogen,

(d) hydroxyethyl,

(e) carboethoxymethyl,

(f) cyclopropyl, or

R₇ and R₈ are joined together to form a substituted ring selected from

(a) piperidinyl, and

(b) morpholinyl, or

R₈ and R₉ are joined together to form a piperazine ring.

In another aspect the present invention is directed to the treatment of leukemia, such as nonlymphoblastic leukemias, acute myelogenous leukemia (FAB M1 and FAB M2), acute promyelocytic leukemia (FAB M3), acute myelomonocytic leukemia (FAB M4), acute monocytic leukemia (FAB M5), erythroleukemia, chronic myelogenous leukemia, chronic myelomonocytic leukemia, chronic monocytic leukemia and conditions associated with leukemia involving activity of PMN neutral proteases e.g. disseminated intravascular coagulation with compounds of Formula I.

Treatment of leukemia cells comprises: administration of a therapeutically effective amount of a compound of Formula I results in the inhibition of proteinase 3/myeloblastin, inhibition of elastase, inhibition of proliferation of the leukemia cells, induction of differentiation of the leukemia cells, and remission of the disease state.

In one alternative embodiment the invention concerns a method of treating leukemia comprising: administration to a patient in need of such treatment of a therapeutically effective amount of compound of Formula I.

In a second alternative embodiment the invention concerns a method of inhibiting proteinase 3/myeloblastin, comprising: administration to a patient in need of such inhibition of a therapeutically effective amount of compound of Formula I as defined above.

In a third alternative embodiment the invention concerns a method of inhibiting proteinase 3/myeloblastin and elastase, comprising: administration to a patient in need of such inhibition of a therapeutically effective amount of compound of Formula I as or a pharmaceutically acceptable salt thereof as defined above.

In a fourth embodiment the invention concerns a method of inducing cellular differentiation in leukemia cells comprising: administration to a patient in need of such inhibition of a therapeutically effective amount of compound of Formula I or a pharmaceutically acceptable salt thereof as defined above.

Each of the above alternative embodiments (i.e., those relating to PR3 or cancer), also concerns co-administration of a compound of Formula I as defined above, with an agent or agents known in the art for treatment of leukemia, including, but not limited to epsilon-aminocaproic acid, heparin, trasylol (aprotinin); prednisolone; cytosine arabinoside; β-mercaptopurine; cytarabine; an anthracycline (see Young et. al. (1981) N. Engl. J. Med. 305:139) such as daunorubicin, doxorubicin and epidoxorubicin; Vitamin A derivatives including retinoids and all-trans-retinoic acid (See Ellison R. R. et.al. (1968) Blood 32:507, Arabinosyl Cytosine: A useful agent in the treatment of leukemia in adults; Cytarabine: Therapeutic new dimensions, Semin. Oncol. 12:1 (1985, supp 3); Weinstein H. J. et. al. (1983) Blood 62:315, Chemotherapy for acute myelogenous leukemia in children and adults results in an enhanced therapeutic response.

Accordingly, in a fifth alternative embodiment the invention concerns a pharmaceutical composition comprising: a pharmaceutical carrier, a therapeutically effective amount of compound selected from the group consisting of epsilon-aminocaproic acid, heparin, trasylol, prednisolone, cytosine arabinoside, β-mercaptopurine, cytarabine, an anthracycline and a vitamin A derivative; and a therapeutically effective amount of compound of Formula I as defined above.

In a sixth alternative embodiment the invention concerns a method of treating leukemia comprising: co-administration to a patient in need of such treatment of a therapeutically effective amount of compound selected from the group consisting of epsilon-aminocaproic acid, heparin, trasylol, prednisolone, cytosine arabinoside, b-mercaptopurine, cytarabine, an anthracycline, and a vitamin A derivative; and a therapeutically effective amount of compound of Formula I as defined above.

In a seventh alternative embodiment the invention concerns a method of inhibiting proteinase 3/myeloblastin, comprising:

co-administration to a patient in need of such inhibition of a therapeutically effective amount of compound selected from the group consisting of epsilon-aminocaproic acid, heparin, trasylol, prednisolone, cytosine arabinoside, β-mercaptopurine, cytarabine, an anthracycline, and a vitamin A derivative;and a therapeutically effective amount of compound of Formula I as defined above.

In an eighth alternative embodiment the invention concerns a method of inhibiting proteinase 3/myeloblastin and elastase, comprising: administration to a patient in need of such inhibition of a therapeutically effective amount of compound selected from the group consisting of epsilon-aminocaproic acid, heparin, trasylol, prednisolone, cytosine arabinoside, β-mercaptopurine, cytarabine, an anthracycline, and a vitamin A derivative; and a therapeutically effective amount of compound of Formula I as defined above.

In a ninth alternative embodiment the invention concerns a method of inducing cell differentiation in leukemia cells comprising: administration to a patient in need of such inducing of a therapeutically effective amount of compound selected from the group consisting of epsilon-aminocaproic acid, heparin, trasylol, prednisolone, cytosine arabinoside, β-mercaptopurine, cytarabine, an anthracycline and a vitamin A derivative; and a therapeutically effective amount of compound of Formula I as defined above.

The compounds of the invention are prepared by known methods or are prepared among other methods by the following representative schemes. For example, methods for making such compounds are disclosed in EP 0 337 549, published Oct. 18, 1989, which is hereby incorporated by reference.

This invention also relates to a method of treating inflammation in patients using a compound of Formula (I), particularly a preferred compound as the active constituent.

It has been found that the following compound are effective inhibitors of the proteolytic function of human neutrophil elastase as shown below in Table 1 to 10.

                  TABLE 1                                                          ______________________________________                                          ##STR21##                                                                     No.  A                         Kobs/[I]                                        ______________________________________                                          1   CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                                      1,566,000                                        2   CH.sub.2 CO.sub.2 H       1,667,000                                        3   CH.sub.2 C(O)N(CH.sub.2 CH.sub.2 OH).sub.2                                                               3,428,000                                        4   CH.sub.2 C(O)N(CH.sub.3)CH.sub.2 C(O)NH.sub.2                                                            4,293,000                                        5   CH.sub.2 C(O)NHC(CH.sub.2 OH).sub.3                                                                      4,448,000                                        6   CH.sub.2 C(O)N(CH.sub.3).sub.2                                                                           2,997,000                                        7   CH.sub.2 CH.sub.2 N(CH.sub.3)Ac                                                                          1,558,000                                        8   CH.sub.2 C(O)-Pro-OCH.sub.2 Ph                                                                           12,501,000                                       9   CH.sub.2 C(O)-Pro-OH      1,571,000                                       10   CH(CH.sub.3)CO.sub.2 CH.sub.2 Ph                                                                         2,891,000                                       11   CH(CH.sub.3)CO.sub.2 H    1,132,000                                       12   CH(CH.sub.3)C(O)N(Et).sub.2                                                                              2,815,000                                       13   CH(CH.sub.3)CH.sub.2 N(CH.sub.3).sub.2                                                                   2,472,000                                       14   CH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                             2,855,000                                       15   CH.sub.2 CH.sub.2 N(O)(CH.sub.3).sub.2                                                                   2,162,000                                       16   CH.sub.2 CH.sub.2 N(Et).sub.2                                                                            2,291,000                                       17   CH.sub.2 CH.sub.2 (4-morpholinyl)                                                                        4,733,000                                       18   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                    1,934,000                                       19   CH.sub.2 C(O)-Pro-NHCH.sub.2 Ph                                                                          4,956,000                                       20   CH.sub.2 C(CH.sub.3).sub.2 N(CH.sub.3).sub.2                                                             1,470,000                                       21   CH.sub.2 CH.sub.2 N(i-Pr).sub.2                                                                          1,671,000                                       22   CH.sub.2 CH.sub.2 (4-carbobenzyloxy-1-piperazinyl)                                                       4,115,000                                       23   CH.sub.2 CH.sub.2 N(n-Bu).sub.2                                                                          992,000                                         24   CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub          .2                        1,988,000                                       25   CH.sub.2 CH.sub.2 (1-piperazinyl)                                                                        1,709,000                                       26   CH.sub.2 CH.sub.2 (4-methyl-1-piperazinyl)                                                               4,685,000                                       27   CH.sub.2 CH.sub.2 (4-acetyl-1-piperazinyl)                                                               3,262,000                                       28   CH.sub.2 CH.sub.2 N(Ph).sub.2                                                                            188,000                                         29   CH.sub.2 CH.sub.2 N(CH.sub.2 CHCH.sub.2).sub.2                                                           891,000                                         30   CH.sub.2 CH(Ph)N(CH.sub.3).sub.2                                                                         656,000                                         31   CH.sub.2 CH.sub.2 N(CH.sub.3)CH.sub.2 Ph                                                                 1,180,000                                       ______________________________________                                    

                  TABLE 2                                                          ______________________________________                                          ##STR22##                                                                     No.      A                 Kobs/[I]                                            ______________________________________                                         32       CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                              1,993,000                                           33       CH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                     1,151,000                                           34       CH.sub.2 CH.sub.2 N(Et).sub.2                                                                    1,339,000                                           35       CH.sub.2 CH.sub.2 -(4-morpholinyl)                                                               1,725,000                                           36       CH(CH.sub.3)CH.sub.2 N(CH.sub.3).sub.2                                                           1,688,000                                           37       CH.sub.2 C(CH.sub.3).sub.2 N(CH.sub.3).sub.2                                                     2,100,000                                           38       CH.sub.2 CO.sub.2 H                                                                              1,008,000                                           39       CH.sub.2 CH.sub.2 N(CH.sub.3)CH.sub.2 Ph                                                           751,000                                           ______________________________________                                    

                  TABLE 3                                                          ______________________________________                                          ##STR23##                                                                     No.    A                       Kobs/[I]                                        ______________________________________                                         40     N(CH.sub.2 CH.sub.2 OH).sub.2                                                                          1,241,000                                       41     4-methyl-1-piperazinyl  974,000                                         42     4-morpholinyl           1,088,000                                       43     NHCH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                                  1,211,000                                       44     N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                         1,243,000                                       45     NHCH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                         1,118,000                                       46     NHCH.sub.2 CH.sub.2 -(4-pyridyl)                                                                       2,254,000                                       47     NHCH.sub.2 CO.sub.2 H   876,000                                         48     NHCH(CH.sub.3)CO.sub.2 H                                                                               676,000                                         49     NHCH.sub.2 C(O)N(CH.sub.2 CH.sub.2 OH).sub.2                                                           1,295,000                                       50     N(CH.sub.3)CH.sub.2 CO.sub.2 H                                                                         989,000                                         51     NHCH(CH.sub.3)C(O)N(CH.sub.2 CH.sub.2 OH).sub.2                                                        939,000                                         52     N(CH.sub.3)CH.sub.2 C(O)N(CH.sub.2 CH.sub.2 OH).sub.2                                                  273,000                                         53     N(CH.sub.3)CH.sub.2 CH.sub.2 -(4-morpholinyl)                                                          2,511,000                                       54     N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.2 CH.sub.2 OCH.sub.3).sub.2                                      1,388,000                                       55     N(CH.sub.3)CH.sub.2 CH.sub.2 N(Et).sub.2                                                               1,316,000                                       56     N(CH.sub.3)CH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                1,047,000                                       57     NHCH.sub.2 CH(CH.sub.3)N(CH.sub.3).sub.2                                                               1,344,000                                       58     N(CH.sub.3)CH.sub.2 CH.sub.2 N(i-Pr).sub.2                                                             1,634,000                                       59     N(n-Pr).sub.2           1,144,000                                       60     N(Et).sub.2             1,079,000                                       61     3-chloroanilino-        733,000                                         62     3-methoxyanilino-       1,621,000                                       63     4-fluoroanilino-                                                        64     N(CH.sub.3)CH.sub.2 CH.sub.2 CH.sub.2 CO.sub.2 H                                                       917,000                                         65     N(CH.sub.3)CH.sub.2 CH.sub.2 CH.sub.2 C(O)NHSO.sub.2 Ph                                                1,335,000                                       66     N(CH.sub.3)CH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3)CH.sub.2 Ph                                           1,355,000                                       67     N(CH.sub.3).sub.2       942,000                                         68     N(CH.sub.3)CH.sub.2 Ph  1,897,000                                       69     N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)CH.sub.2 Ph                                                    2,792,000                                       70     NHOCH.sub.2 Ph          2,371,000                                       71     N(CH.sub.3)(4-carboxyphenyl)                                                                           1,508,000                                       72     N(CH.sub.3)(4-benzenesulfonyl-                                                                         3,284,000                                              amino-carbonylphenyl)                                                   ______________________________________                                    

                  TABLE 4                                                          ______________________________________                                          ##STR24##                                                                     No.  A                          Kobs/[I]                                       ______________________________________                                         73   NHCH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                                     968,000                                        74   NHCH.sub.2 CO.sub.2 H      1,434,000                                      75   N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                            1,916,000                                      76   N(Et)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                                  1,436,000                                      77   NHCH.sub.2 CH.sub.2 N(Et).sub.2                                                                           1,187,000                                      78   NHCH.sub.2 CH.sub.2 -(4-morpholinyl)                                                                      1,841,000                                      79   N(CH.sub.3)CH.sub.2 CH.sub.2 -(4-morpholinyl)                                                             2,118,000                                      80   N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.2 CH.sub.2 OCH.sub.3).sub.2                                         2,078,000                                      81   N(CH.sub.3)CH.sub.2 CH.sub.2 N(Et).sub.2                                                                  2,191,000                                      82   N(Ph)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                                  2,504,000                                      83   N(CH.sub.3)CH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                   1,797,000                                      84   NHCH.sub.2 CH.sub.2 N(i-Pr).sub.2                                                                         2,100,000                                      85   N(CH.sub.3)CH.sub.2 CH.sub.2 N(O)(CH.sub.3).sub.2                                                         1,589,000                                      86   N(CH.sub.3)CH.sub.2 CH.sub.2 N(i-Pr).sub.2                                                                2,449,000                                      87   NHSO.sub.2 CH.sub.2 CH.sub.2 -(4-morpholinyl)                                                             775,000                                        88   NHSO.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                            788,000                                        89   NHCH.sub.2 CH.sub.2 -(4-imidazolyl)                                                                       2,092,000                                      90   NHCH.sub.2 CH.sub.2 -(1-piperidinyl)                                                                      941,000                                        91   N(CH.sub.3)CH.sub.2 CH.sub.2 -(1-piperidinyl)                                                             892,000                                        92   N(CH.sub.3)CH.sub.2 CH.sub.2 NHCH.sub.3                                                                   1,453,000                                      93   N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)Ac                                                                1,960,000                                      94   NHCH.sub.2 CH.sub.2 -(1-pyrrolidinyl)                                                                     1,239,000                                      95   N(CH.sub.3)CH.sub.2 CH.sub.2 -(1-pyrrolidinyl)                                                            1,005,000                                      96   NHCH.sub.2 CH.sub.2 -(1H-1,2,4-triazol-1-yl)                                                              1,397,000                                      97   NHCH.sub.2 CH.sub.2 -(1-imidazolyl)                                                                       1,070,000                                      98   NHCH.sub.2 CH.sub.2 -(3-azabicyclo-[3.2.2-non-3-yl)                                                       3,043,000                                      99   NHCH.sub.2 CH.sub.2 -(3-azaspiro[5.5]-undec-3-yl)                                                         2,583,000                                      100  NHCH.sub.2 CH.sub.2 -(2H-tetrazol-2-yl)                                                                   2,006,000                                      101  NHCH.sub.2 CH.sub.2 -(1H-tetrazol-1-yl)                                                                   2,053,000                                      102  NHCH.sub.2 C(O)-Pro-NHCH.sub.2 Ph                                                                         2,747,000                                      103  N(CH.sub.3)CH.sub.2 CH.sub.2 -(3-azabicyclo-                                                              2,996,000                                           [3.2.2]non-3-yl)                                                          104  N(CH.sub.3)CH.sub.2 CH.sub.2 -(4-imidazolyl)                                                              2,389,000                                      105  N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)Ac                                                                2,398,000                                      106  N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)C(O)NHCH.sub.3                                                    2,486,000                                      107  N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)SO.sub.2 CH.sub.3                                                 2,530,000                                      108  N(CH.sub.3)CH.sub.2 CH.sub.2 (3-azabicyclo-[3.2.2]-                                                       2,953,000                                           non-3-yl)                                                                 109  NHCH.sub.2 CH.sub.2 -(1,1-dioxo-4-thiamorpholinyl)                                                        1,275,000                                      110  4-dimethylaminobenzylamino 5,598,000                                      111  3-dimethylaminoanilino     2,286,000                                      112  N(CH.sub.3)CH.sub.2 CH.sub.2 -(1,1-dioxo-4-thia-                                                          1,596,000                                           morpholinyl)                                                              113  4-dimethylaminoanilino     2,591,000                                      114  NHCH.sub.2 CH.sub.2 -(1-benzyl-1H-imidazol-2-yl)                                                          3,853,000                                      115  N(CH.sub.3)CH.sub.2 CH.sub.2 (2-pyridyl)                                                                  2,272,000                                      116  N(CH.sub.3)(1-azabicyclo[2.2.2]oct-3-yl                                                                   3,480,000                                      117  NHCH.sub.2 CH.sub.2 (4-benzyloxycarbonyl-1-                                                               6,231,000                                           piperazinyl)                                                              118  1,2-diethylpyrazolidin-4-ylamino                                                                          1,001,000                                      119  2-(1- S-pyrrolidinylmethyl)-1-pyrrolidinyl                                                                2,692,000                                      120  NHCH.sub.2 CH.sub.2 (4-hydroxy-1-piperidinyl)                                                             1,728,000                                      121  NHCH.sub.2 CH.sub.2 (1-homopiperidinyl)                                                                   2,069,000                                      122  N(CH.sub.3)CH.sub.2 CH.sub.2 (1-homopiperidinyl)                                                          2,899,000                                      123  NHCH.sub.2 CH.sub.2 (3-hydroxy-1-piperidinyl)                                                             1,534,000                                      124  N(CH.sub.3)CH.sub.2 CH.sub.2 (3-hydroxy-1-piperidinyl)                                                    1,963,000                                      125  N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)CH.sub.2 Ph                                                       2,054,000                                      126  N(CH.sub.3)CH.sub.2 CH.sub.2 (4-benzyloxy-1-piperidinyl)                                                  3,476,000                                      127  N(n-Pr).sub.2              990,000                                        128  N(Et).sub.2                1,454,000                                      129  N(CH.sub.3)CH.sub.2 CH.sub.2 (4-hydroxy-1-piperidinyl)                                                    1,994,000                                      130  N(CH.sub.3)CH.sub.2 CH.sub.2 (4-oxo-1-piperidinyl)                                                        2,297,000                                      131  NHCH.sub.2 CH.sub.2 (3-hydroxy-1-pyrrolidinyl)                                                            1,111,000                                      132  N(Et)CH.sub.2 CH.sub.2 (1-piperidinyl)                                                                    1,244,000                                      133  N(CH.sub.2 Ph)CH.sub.2 CH.sub.2 (1-piperidinyl)                                                           1,521,000                                      134  4-fluoroanilino-           724,000                                        135  3-chloroanilino-           201,000                                        136  3-methoxyanilino                                                          137  N(CH.sub.2 Ph)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                         1,380,000                                      138  N(CH.sub.3)CH.sub.2 CH.sub.2 (3-hydroxy-1-pyrrolidinyl)                                                   960,000                                        139  N(3-picolyl)CH.sub.2 CH.sub.2 (1-piperidinyl)                                                             1,189,000                                      140  NHCH(CH.sub.3)CH.sub.2 CH.sub.2 CH.sub.2 N(Et).sub.2                                                      1,361,000                                      141  NHCH.sub.2 CH.sub.2 (2- S-hydroxymethyl-1-                                                                1,507,000                                           pyrrolidinyl                                                              142  N(CH.sub.3)CH.sub.2 CH.sub.2 (4-t-butoxycarbonyl-1-                                                       3,471,000                                           piperazinyl)                                                              143  N[CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2 ].sub.2                                                             1,878,000                                      144  N[CH.sub.2 CH.sub.2 N(Et).sub.2 ].sub.2                                                                   1,508,000                                      145  N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(3-picolyl)                                                       2,877,000                                      146  3,5-dimethyl-1-piperazinyl 1,518,000                                      147  N(CH.sub.3)CH.sub.2 CH.sub.2 N(O)(CH.sub.3)CH.sub.2 Ph                                                    2,493,000                                      148  N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(4-picolyl)                                                       2,389,000                                      149  2- S-(N-benzylN-methylaminomethyl)-1-                                                                     3,268,000                                           pyrrolidinyl                                                              150  N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(2-picolyl)                                                       2,165,000                                      151  N(CH.sub.3)CH.sub.2 CH.sub.2 (1-piperazinyl)                                                              1,191,000                                      152  1-homopiperazinyl          1,951,000                                      153  N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)CH.sub.2 CH.sub.2 Ph                                              2,797,000                                      154  2-(1-R-pyrrolidinylmethyl)-1-pyrrolidinyl                                                                 1,666,000                                      155  4-benzyl-1-homopiperazinyl 1,979,000                                      156  N(CH.sub.3)CH.sub.2 [CH(OH)].sub.4 CH.sub.2 OH                                                            1,198,000                                      157  N(CH.sub.3)CH.sub.2 [CH(OAc)].sub.4 CH.sub.2 OAc                                                          1,171,000                                      158  N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(1-Naphthalenyl-                                                  1,075,000                                           methyl)                                                                   159  N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(2-Naphthalenyl-                                                  1,337,000                                           methyl)                                                                   160  N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)CH(CH.sub.3)Ph                                                    1,569,000                                      161  N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.2 Ph).sub.2                                                         1,021,000                                      162  1-ethyl-3-piperidinylamino 949,000                                        163  N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(2-furfuryl)                                                      1,818,000                                      164  N(CH.sub.3)CH.sub.2 CH.sub.2 CH.sub.2 CO.sub.2 H                                                          1,064,000                                      165  N(CH.sub.3)CH.sub.2 CH.sub.2 CH.sub.2 C(O)NHSO.sub.2 Ph                                                   1,550,000                                      166  N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)CH.sub.2 CHCH.sub.2                                               1,359,000                                      167  N(CH.sub.3)CH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3)CH.sub.2 Ph                                              1,293,000                                      168  N(CH.sub.3)(CH.sub.2).sub.6 N(CH.sub.3)CH.sub.2 Ph                                                        2,157,000                                      169  N(CH.sub.3)CH.sub.2 CH.sub.2 OH                                                                           1,457,000                                      170  N(CH.sub.3)CH.sub.2 CH.sub.2 OC(O)N(CH.sub.3).sub.2                                                       1,518,000                                      171  N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)CH.sub.2 CO.sub.2 -t-Bu                                           1,831,000                                      172  N(CH.sub.3)(1-ethyl-3-piperidinyl)                                                                        1,545,000                                      173  N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(tetrahydro-2H-                                                   2,943,000                                           pyran-2-yl-methyl)                                                        174  2,2,6,6-tetramethylpiperidin-4-ylamino                                                                    869,000                                        175  N(CH.sub.3)(4-carboxyphenyl)                                                                              1,055,000                                      176  N(CH.sub.3)(4-benzenesulfonylaminocarbonyl-                                                               3,231,000                                           phenyl                                                                    177  N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(4-cyanobenzyl)                                                   2,201,000                                      178  N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(4-methylbenzyl)                                                  1,870,000                                      179  N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(3-cyanobenzyl)                                                   2,448,000                                      180  N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(4-trifluoro-                                                     905,000                                             methylbenzyl                                                              181  N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(3-trifluoromethyl-                                               564,000                                             benzyl)                                                                   182  N(CH.sub.3)CH.sub.2 CH.sub.2 (CH.sub.3)(4-fluorobenzyl)                                                   2,137,000                                      183  NHCH(CH.sub.3)PH(O)OH      977,000                                        184  L-lysine ((α-N)      755,000                                        185  N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(cyclopropylmethyl)                                               1,787,000                                      186  N(CH.sub.3)CH.sub.2 CH(Ph)N(CH.sub.3).sub.2                                                               1,053,000                                      187  N(CH.sub.3).sub.2          1,749,000                                      188  N(CH.sub.3)CH.sub.2 Ph     1,837,000                                      189  N(CH.sub.3)(1-benzyl-3-piperidinyl)                                                                       1,879,000                                      190  NHOCH.sub.2 Ph             1,797,000                                      191  N(3-picolyl)CH.sub.2 CH.sub.2 N(CH.sub.3)CH.sub.2 Ph                                                      2,538,000                                      192  N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(4-methoxybenzyl)                                                 1,785,000                                      193  N(4-picolyl)CH.sub.2 CH.sub.2 N(CH.sub.3)CH.sub.2 Ph                                                      2,243,000                                      194  N(2-picolyl)CH.sub.2 CH.sub.2 N(CH.sub.3)CH.sub.2 Ph                                                      2,473,000                                      195  N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(2,4-dimethylbenzyl)                                              1,119,000                                      196  N(CH.sub.3)CH.sub.2 CH.sub.2 (2,6-dimethyl-4-morpholinyl)                                                 1,530,000                                      197  NH.sub.2                   1,638,000                                      198  NHCH.sub.3                 1,825,000                                      199  4-morpholinyl              2,376,000                                      200  cis-2,6-dimethyl-4-morpholinyl                                                                            1,837,000                                      201  NHCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                                     2,460,000                                      202  N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)C(NCN)NHPh                                                        1,763,000                                      203  N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(3-fluorobenzyl)                                                  1,262,000                                      204  N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(2-chlorobenzyl)                                                  1,591,000                                      205  N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(3-methoxybenzyl)                                                 1,911,000                                      206  N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(3,5-dimethoxy-                                                   1,735,000                                           benzyl)                                                                   207  3,4-dihydro-6,7-dimethoxy-2-(1H)iso-                                                                      2,698,000                                           quinolinyl                                                                208  N(CH.sub.3)(1-benzyl-4-piperidinyl)                                                                       1,948,000                                      209  L-lysine (ε-N)     929,000                                        210  N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(2-adamantyl)                                                     2,132,000                                      211  N(CH.sub.3)(4-piperidinyl) 85,000                                         212  5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl                                                                 860,000                                        213  N(CH.sub.3)CH.sub.2 CO.sub.2 H                                                                            984,000                                        214  N(CH.sub.3)CH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3)CH.sub.2 CH.sub.3                                        1,099,000                                      215  N(CH.sub.3)(1-methyl-4-piperidinyl)                                                                       1,283,000                                      216  N(CH.sub.3)(1-propyl-4-piperidinyl)                                                                       1,312,000                                      217  N(CH.sub.3)(1-ethyl-4-piperidinyl)                                                                        1,422,000                                      218  N(CH.sub.3)CH.sub.2 CH(CH.sub.3)N(CH.sub.3)CH.sub.2 Ph                                                    2,123,000                                      219  N(CH.sub.3)CH.sub.2 CH(CH.sub.3)N(CH.sub.3).sub.2                                                         1,588,000                                      220  N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(bicyclo[2.2.1]-                                                  1,874,000                                           hept-2-yl)                                                                221  N(CH.sub.3)CH.sub.2 CH.sub.2 NH(2-adamantyl)                                                              3,010,000                                      222  N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(6,6-dimethylbicyclo-                                             2,288,000                                           [3.1.1]hept-2-yl                                                          223  N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(bicyclo[3.2.1]-                                                  2,584,000                                           oct-2-yl)                                                                 224  NH(t-Bu)                                                                  225  N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(1-cyclohexen-1-yl)                                               1,839,000                                      226  N(CH.sub.3)CH.sub.2 CH.sub.2 NHC(CH.sub.3).sub.2 CHCH.sub.2                                               1,309,000                                      227  2- S-carboxamido-1-pyrrolidinyl                                                                           931,000                                        228  2-hydroxymethyl-1-piperidinyl                                                                             50,000                                         229  3-dimethylamino-1-pyrrolidinyl                                                                            1,336,000                                      230  N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(cyclohexylmethyl)                231  N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.2 CHCH.sub.2)C(CH.sub.3).sub.2           CHCH.sub.2                 925,000                                        232  N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(4-ethylcyclohexyl)                                               2,476,000                                      233  N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(2-ethylcyclohexyl)                                               2,030,000                                      234  N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(4-methylcyclohexyl)                                              2,166,000                                      235  N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)(cyclohexyl)                                                      1,952,000                                      236  N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)CH.sub.2 CO.sub.2 H.TFA                                           31,000                                         237  N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)CH.sub.2 C(O)N(CH.sub.3).sub.          2                          2,679,000                                      238  3-dimethylamino-1-azetidinyl                                              239  1-diphenylmethyl-3-azetidinyl                                             240  N(CH)CH.sub.2 CH.sub.2 N(CH.sub.3)(cyclohexylmethyl)                                                      3,003,000                                      241  NHCH.sub.2 CH.sub.2 N(Et)CH.sub.2 CH.sub.2 OCH.sub.3                                                      1,090,000                                      ______________________________________                                    

                  TABLE 5                                                          ______________________________________                                          ##STR25##                                                                     No.       R                Kobs/[I]                                            ______________________________________                                         242       CH.sub.3         1,700,000                                           243       4-fluorophenyl   7,486,000                                           244       3-chlorophenyl   2,453,000                                           245       phenyl           5,276,000                                           246       benzyl           5,171,000                                           247       H                1,100,000                                           248       i-Pr             2,392,000                                           249       i-Bu             2,476,000                                           250       CH.sub.2 CO.sub.2 Et                                                                            1,571,000                                           251       CH.sub.2 CO.sub.2 H                                                                             1,947,000                                           252       Et               2,324,000                                           253       Pr               1,768,000                                           254       2-pyrimidinyl    2,142,000                                           255       CH.sub.2 CH.sub.2 OC(O)NHCH.sub.3                                                               2,548,000                                           256       Cyclopropyl      3,587,000                                           256a      CH.sub.2 CH.sub.2 OH                                                                            2,000,000                                           ______________________________________                                    

                  TABLE 6                                                          ______________________________________                                          ##STR26##                                                                     No.  n       A                    Kobs/[I]                                     ______________________________________                                         257  1       NH.sub.2             2,342,000                                    258  1       4-morpholinyl        1,785,000                                    259  1       N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                      2,522,000                                    260  0       N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                      3,317,000                                    261  0       N(Et).sub.2          3,207,000                                    262  0       N(CH.sub.3)(n-Bu)    3,125,000                                    263  0       4-methyl-1-piperazinyl                                                                              3,805,000                                    264  0       N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)CH.sub.2 Ph                                                 3,427,000                                    265  0       4-cyclopropyl-1-piperazinyl                                                                         4,500,000                                    265a 0       1-piperazinyl        3,250,000                                    265c 0       4-(2-hydroxyethyl)-1-piperazinyl                                                                    4,800,000                                    265d 0       4-morpholinyl        3,700,000                                    ______________________________________                                    

                  TABLE 7                                                          ______________________________________                                          ##STR27##                                                                     No.  n       R.sub.4 A               Kobs/[I]                                  ______________________________________                                         266  1       H       4-morpholinyl   169,000                                   267  1       H       N(Et).sub.2     334,000                                   268  1       H       N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                 142,000                                   269  1       CH.sub.3                                                                               NH.sub.2        637,000                                   270  1       CH.sub.3                                                                               N(Et).sub.2     740,000                                   271  1       CH.sub.3                                                                               N(n-Pr).sub.2   826,000                                   272  0       Et      N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                 2,423,000                                 273  0       Et      N(CH.sub.3)(n-Bu)                                                                              3,258,000                                 ______________________________________                                    

                  TABLE 8                                                          ______________________________________                                          ##STR28##                                                                     No.   n     R.sub.3 A               Kobs/[I]                                   ______________________________________                                         274   1     H       NH.sub.2        430,000                                    275   1     H       N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                 290,000                                    276   1     H       OCH.sub.3       440,000                                    277   0     H       N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                 548,000                                    278   0     R       OCH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                           135,000                                    279   0     H       N(Et).sub.2     566,000                                    280   0     H       4-morpholinyl   577,000                                    ______________________________________                                    

                                      TABLE 9                                      __________________________________________________________________________      ##STR29##                                                                     No.                                                                               n R.sub.3   R.sub.2         A                Kobs/[I]                       __________________________________________________________________________     281                                                                               1 H         CO.sub.2 H      4-morpholinyl    62,000                         282                                                                               1 H         CO.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                   4-morpholinyl    421,000                        283                                                                               1 H         CON(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                               4-morpholinyl    393,000                        284                                                                               1 H         OH              N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).su                                    b.2              309,000                        285                                                                               1 H         OCH.sub.3       N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).su                                    b.2              566,000                        286                                                                               0 H         CON(CH.sub.3).sub.2                                                                            N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).su                                    b.2              551,000                        287                                                                               0 H         CO.sub.2 H      N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).su                                    b.2              113,000                        288                                                                               0 H         CH.sub.2 OH     N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).su                                    b.2              854,000                        289                                                                               1 H         OCH.sub.3       N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).su                                    b.2              754,000                        290                                                                               0 H         OCH.sub.3       N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).su                                    b.2              1,010,000                      291                                                                               0 OCH.sub.3 H               N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).su                                    b.2              1,754,000                      292                                                                               1 CH.sub.2 OCON(Et).sub.2                                                                  CH.sub.3        4-morpholinyl    807,000                        293                                                                               1 CON(n-Pr).sub.2                                                                          CH.sub.3        N(Et).sub.2      457,000                        294                                                                               1 CON(n-Pr).sub.2                                                                          CH.sub.3        4-morpholinyl    255,000                        295                                                                               0 H         CN              N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).su                                    b.2              846,000                        296                                                                               0 H         OEt             N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)CH.                                    sub.2 Ph         776,000                        297                                                                               0 H         2-(4-morpholinocarbonylphenyl)                                                                 N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)CH.                                    sub.2 Ph         1,077,000                      298                                                                               0 H         OCH.sub.3       4-methyl-1-piperazinyl                                                                          1,845,000                      299                                                                               0 H         Cl              N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).su                                    b.2              1,475,000                      300                                                                               0 H         Cl              N(CH.sub.3)CH.sub.2 CH.sub.2 N(Et).sub.2                                                        1,282,000                      301                                                                               0 H         Cl              N(CH.sub.3)CH.sub.2 CH.sub.2 N(i-Pr).sub.2                                                      1,497,000                      302                                                                               0 H         Cl              N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)CH.                                    sub.2 Ph         1,462,000                      303                                                                               0 OCH.sub.3 CH.sub.3        N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).su                                    b.2                                             __________________________________________________________________________

                  TABLE 10                                                         ______________________________________                                          ##STR30##                                                                     No.   R.sub.2 R.sub.6 A               Kobs/[I]                                 ______________________________________                                         304   CH.sub.3                                                                               CH.sub.3                                                                               OCH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                           563,000                                  305   CH.sub.3                                                                               CH.sub.3                                                                               OCH.sub.2 CH.sub.2 N(Et).sub.2                                                                 749,000                                  306   CH.sub.3                                                                               CH.sub.3                                                                               OCH.sub.2 CH.sub.2 N(i-Pr).sub.2                                                               612,000                                  307   CH.sub.3                                                                               CH.sub.3                                                                               N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                 352,000                                  308   CH.sub.3                                                                               CH.sub.3                                                                               N(CH.sub.3)CH.sub.2 CH.sub.2 N(Et).sub.2                                                       377,000                                  309   CH.sub.3                                                                               CH.sub.3                                                                               N(Et)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                       398,000                                  310   H       OH      N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                 838,000                                  ______________________________________                                    

Enzyme Assays for the Inhibition of Human Polymorphonuclear Leukocyte Elastase Via Hydrolysis of N-t-Boc-alanyl-alanyl-prolylalanine-p-nitroanilide (Boc-AAPAN) or N-t-Boc-alanyl-prolylvaline-p-nitroanilide (Boc-AAPVN) Reagent:

0.05M TES (N-tris[hydroxymethyl]methyl-2-mino-ethanesulfonic acid) Buffer, pH 7.5.

0.2 mM Boc-AAPAN or Boc-AAPVN.

To prepare substrate, the solid was first dissolved in 10.0 ml DMSO. Buffer at pH 7.5 was then added to a final volume of 100 ml.

Crude extract of human polymorphonuclear leukocytes (PMN) containing elastase activity.

Inhibitors (azetidinones) to be tested dissolved in DMSO just before use.

To 1.0 ml of 0.2 mM Boc-AAPAN in a cuvette, 0.01-0.1 ml of DMSO with or without inhibitor was added. After mixing, a measurement was taken at 410 mμ to detect any spontaneous hydrolysis due to presence of test compound. 0.05 Milliliters of PMN extract was then added and the ΔOD/min at 410 mμ was measured and recorded. Beckman model 35 spectrophotometer was used.

Results were expressed to the nearest thousand ^(k) obs/I which is the second order rate constant in per mole per second for inactivation of the enzyme.

The elastase activity in the crude PMN extract may vary from one preparation to another. A control of each new batch is run, and the volume added in the assay procedure is adjusted according to activity.

This invention also relates to a method of treating inflammation in patients using a compound of Formula (I), particularly a preferred compound as the active constituent.

It has been found that the compounds of Formula (I) are effective inhibitors of the proteolytic function of human neutrophil elastase.

Accordingly, the compounds of Formula (I), can be used to reduce inflammation and/or relieve pain in diseases such as emphysema, rheumatoid arthritis, osteoarthritis, gout, bronchial inflammation, chronic or acute bronchitis, cystic fibrosis, adult respiratory distress syndrome, atherosclerosis, sepsis, septicemia, shock, periodontitis, glomerular nephritis or nephosis, myocardial infarction, reperfusion injury, infectious arthritis, rheumatic fever and the like, and may reduce hemorrhage in acute promyelocytic leukemia and the like.

In this capacity, and as appreciated by those of skill in the art, therapy comprising administration of compounds of Formula I may actually include co-administration of one or more additional active agents. Classes of active agents include, but are not limited to β₂ -adrenergic agonists; anti-cholinergic agents; steroids; non-steroidal anti-inflammatory agents (NSAID's); mucolytic agents; most all stabilizers; and antibacterials.

For purposes of this specification, β₂ -adrenergic agonists are intended to include, but are not limited to, metaproterenol, terbutaline, isoetharine, albuterol, and ritodrine, carbuterol, fenoterol, quinterenol, rimiterol, salmefamol, soterenol, and tretoquinol.

For purposes of this specification, anti-cholinergic agents are intended to include, but are not limited to, attopine, and iptratropium-bromide.

For purposes of this specification, mucolytic agents are intended to include, but are not limited to acetylcysteine and guattenesin.

For purposes of this specification, steroids are intended to include, but are not limited to, prednisone, beclomethasone, budesonide, solumedrol, triamcinolone, and methyl-prednisolone.

For purposes of this specification most cell stabilizers are intended to include, but are not limited to cromolyn and ketotafin.

For purposes of this specification, nonsteroidal anti-inflammatory agents are intended to include, but are not limited to aspirin, diflunisal, naphthylsalicylate, phenylbutazolone, oxyphenbutazolone, indomethacin, sulindac, mefenamic acid, meclofenamate sodium, tolmetin, ibuprofen, naproxen, fenoprofen and piroxicam.

For the purposes of this specification, antibacterial agents are intended to include the broad classes of penicillins, cephalosporins and other beta-lactams, aminoglycosides, quinolones, macrolides, tetracyclines, sulfonamides, lincosamides and polymyxins. The penicillins, in turn, are intended to include, but are not limited to penicillin G, penicillin V, methicillin, nafcillin, oxacillin, cloxacillin, dicloxacillin, floxacillin, ampicillin, ampicillin/sulbactam, amoxicillin, amoxicillin/clavulanate, hetacillin, cyclacillin, bacampicillin, carbenicillin, carbenicillin indanyl, ticarcillin, ticarcillin/clavulanate, azlocillin, mezlocillin, peperacillin, and mecillinam. The cephalosporins and other beta-lactams are intended to include, but are not limited to cephalothin, cephapirin, cephalexin, cephradine, cefazolin, cefadroxil, cefaclor, cefamandole, cefotetan, cefoxitin, ceruroxime, cefonicid, ceforadine, cefixime, cefotaxime, moxalactam, ceftizoxime, cetriaxome, ceftizoxime, cetriaxone, cephoperazone, ceftazidime, imipenem and aztreonam. The aminoglycosides are intended to include, but are not limited to streptomycin, gentamicin, tobramycin, amikacin, netilmicin, kanamycin and neomycin. The quinolones are intended to include, but are not limited to nalidixic acid, norfloxacin, enoxacin, ciprofloxacin, ofloxacin, sparfloxacin and temafloxacin. The macrolides are intended to include, but are not limited to erythomycin, spiramycin and azithromycin. The tetracyclines are intended to include, but are not limited to doxycycline, minocycline and tetracycline. The sulfonamides are intended to include, but are not limited to sulfanilamide, sulfamethoxazole, sulfacetamide, sulfadiazine, sulfisoxazole and co-trimoxazole (trimethoprim/sulfamethoxazole). The lincosamides are intended to include, but are not limited to clindamycin and lincomycin. The polymyxins (polypeptides) are intended to include, but are not limited to polymyxin B and coilstin.

Alternatively, compounds of Formula I are useful in the treatment of certain cancers including nonlymphoblastic leukemias, acute myelogenous leukemia (FAB M1 and FAB M2), acute promyelocytic leukemia (FAB M3), acute myelomonocytic leukemia (FAB M4), acute monocyte leukemia (FAB M5), erythroleukemia, chronic myelogenous leukemia, chronic myelomonocytic leukemia, chronic monocytic leukemia and conditions associated with leukemia involving activity of PMN neutral proteases e.g. disseminated intravascular coagulation.

Similarly, compounds of Formula I are useful for the inhibition of proteinase 3/myeloblastin, inhibition of elastase, inhibition of proliferation of leukemia cells, inducing differentiation of leukemia cells and remission of the disease state of leukemia.

Moreover, as described above, such treatment may optionally comprise the co-administration of an agent such as a compound selected from the group consisting of epsilon-aminocaproic acid, heparin, trasylol, prednisolone, cytosine arabinoside, b-mercaptopurine, cytarabine, an anthracycline and a vitamin A derivative such as retinoic acid.

For each of the uses, the compounds of Formula (I) and optional treatment agents, may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit Formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition to the treatment of warm-blooded animals such as mice, rats, horses, dogs, cats, etc., the compounds of the invention are effective in the treatment of humans.

For treatment as described above the compounds of Formula (I) may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit Formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition to the treatment of warm-blooded animals such as mice, rats, horses, dogs, cats, etc., the compounds of the invention are effective in the treatment of human.

The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol mono-oleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate. The said aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Oily suspension may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oils, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial. esters derived from fatty acids and hexitol anhydrides, for example sorbitan mono-oleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution glucose in water and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The compounds of Formula (I) may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the anti-inflammatory agents are employed.

The amount of active ingredient(s) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration of humans may contain from 5 mg to 2000 mg or 5000 mg of each active agent(s) compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. For purposes of this specification, this broad dosage range is specifically intended to include, but is not limited to, range of 5 mg to 2000 mg; 25 mg to 2000 mg; 5 mg to 1000 mg; 25 mg to 1000 mg; 5 mg to 500 mg; and 25 mg to 500 mg. Dosage unit forms will generally contain between from about 25 mg to about 500 mg of active ingredient(s).

Furthermore, it is also possible that most effective treatment may warrent administration of an initial dosage of one range (e.g. 1-5 mg of active agent per kg of patient weight) followed by administration of a second range (e.g. 0.1 to 1 mg of active agent per kg of patient weight).

It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

The following example illustrates the preparation of the compounds useful in the method of treatment of the present invention, but does not limit the scope of the invention. Starting materials may be optionally prepared as disclosed in EPO 337 549 published Oct. 18, 1989 which is hereby incorporated by reference. Where appropriate, compounds may be produced and used in the form of pharmaceutically acceptable salts. For example, the basic compounds may be used in the form of a hydrochloride or mesylate or other acceptable salt. See Preformulation in Remington's Pharmaceutical Sciences, Mack Publishing, Easton Pa. ##STR31##

The glycolic acid derivatives described herein can be prepared according to the following scheme. The starting acid (as carboxylate anion) may be alkylated (Ex 1A) with a suitably protected α-halo acetic acid derivative to give the glycolate ester 4 which can be deprotected (Ex 1B) to the glycolic acid ester 5. Treatment of 5 with an amine utilizing a condensing agent such as dicyclohexylcarbodiimide or carbomyldiinidazole (Ex 2) affords the deserved amide 6. Alternately, the starting acid 1 may be converted to its acid chloride 2 (Ex 3A) and treated with a suitably protected α-hydroxyalkanoic acid (Ex 3B) in the presence of base to give the protected ester 7. Deprotection (Ex 4), followed by conversion to the acid chloride and treatment with the appropriate amine (Ex 5) affords the desired amide 9.

EXAMPLE 1

A. t-Butoxycarbonylmethyl [S-(R*,S*)]4-((3,3-diethyl-1-(((1-(4-methylphenyl)butyl)amino)-carbonyl)-4-oxo-2-azetidinyl)oxy)benzoate.

To a solution of 0.806 gm of [S-(R*,S*)]4-((3,3-diethyl-1-(((1-(4-methylphenyl)butyl)amino)carbonyl)-4-oxo-2-azetidinyl)oxy)benzoic acid in ˜3 ml DMF is added 0.23 gm. triethylamine followed by 0.50 gm of t-butyl bromoacetate and the mixture stirred overnight at room temperature. Ethyl acetate (25 ml) is then added and the resultant mixture is washed with 2×10 ml water, 10 ml saturated sodium bicarbonate, and 20 ml brine. The organic layer is dried through sodium sulfate and concentrated in vacuo. Chromatography on Silica gel 60 (350 ml column) and elution with 10% ethyl acetate in hexanes gave 0.67 gm of the t-Butoxycarbonylmethyl [S-(R*,S*)]4-((3,3-diethyl-1-(((1-(4-methylphenyl)butyl)amino)carbonyl)-4-oxo-2-azetidinyl)oxy) benzoate.

In a similar manner can be prepared 2-(dimethylamino)-2-oxoethyl, (S-(R*,S*))-4-((3,3-Diethyl-1-(((1-(4-methyl-phenyl)butyl)amino) carbonyl)-4-oxo-2-azetidinyl)oxy)-benzoate (Compound 6), and 2-(N-methylacetamido)ethyl. {2-(R*,S*)}-4-{{3,3-Diethyl-1-{{{1-(4-methyl-phenyl)butyl}amino}carbonyl}-4-oxo-2-azetidinyl}oxy}-benzoate, (Compound 7).

B. Carboxymethyl [S-(R*,S*)]4-((3,3-diethyl-1-(((1-(4-methyl-phenyl)butyl)amino)carbonyl)-4-oxo-2-azetidinyl)oxy)benzoate

To the above ester is added 2 ml of anisole and the resulting mixture is cooled in an ice bath and 5 ml of ice cold trifluoroacetic acid is added. The reaction mixture is stirred cold for three hours then allowed to come to room temperature. After 30 minutes, the reaction mixture is concentrated in vacuo and the residue chromatographed on silica gel 60. Elution with 20% ethyl acetate in hexanes containing 1% acetic acid gives 0.53 gm of desired carboxymethyl [S-(R*,S*)]4-((3,3-diethyl-1-(((1-(4-methyl- phenyl)butyl)amino)carbonyl)-4-oxo-2-azetidinyl)oxy)benzoate.

Compound 2

Analysis: C₂₈ H₃₄ N₂ O₇ +0.3H₂ O Calc: C, 65.19; H, 6.75; N, 5.43. Found: C, 65.30; H, 6.76; N, 5.23

Compound 6

Analysis: C₃₀ H₃₉ N₃ O₆ +0.5H₂ O Calc: C, 65.91; H, 7.38; N, 7.60 Found: C, 65.71; H, 7.63; N, 7.50.

Compound 7

Analysis: C₃₁ H₄₁ N₃ O₆ +0.6EtOAc Calc: C, 66.35; H, 7.64; N, 6.95 Found: C, 66.52; H, 7.89; N, 6.83.

EXAMPLE 2

2-(bis(2-hydroxyethyl)amino)-2-oxoethyl(S-(R*,S*))-4-((3,3-diethyl-1-(((1-(4-methyl-phenyl)butyl)amino)carbonyl)-4-oxo-2-azetidinyl)oxy)benzoate.

To a solution of 0.125 gm of the acid from 1B in 2-3 ml of methylene chloride is added 0.050 gm of carbonyldiimidazole. The mixture is stirred for 30 minutes at room temperature at which time 0.060 gm of diethanolamine is added along with 1 ml of DMF and 2 ml of methylene chloride. The resulting mixture is stirred overnight at room temperature then concentrated in vacuo. Silica gel chromatography of the residue using 2.5 to 5.0% methanol in methylene chloride gives 0.123 gm of the desired Compound 3, 2-(bis(2-hydroxyethyl)amino)-2-oxoethyl(S-(R*,S*))-4-((3,3-diethyl-1-(((1-(4-methyl-phenyl)butyl)amino)carbonyl)-4-oxo-2-azetidinyl)oxy) benzoate.

Compound 3

Analysis: C₃₂ H₄₃ N₃ O₈, +0.4H₂ O Calc: C, 63.53; H, 7.30; N, 6.95 Found: C, 63,51; H, 7.45; N, 6.95.

Similarly were prepared

Compound 4

Analysis: C₃₁ H₄₀ N₄ O₇ Calc: C, 64.12; H, 6.94; N, 9.65 Found: C, 64.12; H, 7.18; N, 9.44

Compound 5

Analysis: C₃₂ H₄₃ N₃ O₉ +0.3H₂ O Calc: C, 62.08; H, 7.09; N, 6.79 Found: C, 61.89; H, 7.39; N, 6.88.

Compound 8

Analysis: C₄₀ H₄₇ N₃ O₈ Calc: C, 68.85; H, 6.79; N, 6.02 Found: C, 68.79; H, 7.06, N, 5.88.

EXAMPLE 3

Preparation of 1-Methyl-2-oxo-2-(phenylmethoxy)ethyl(2S-(1(S*),R*,(R)))-4-((3,3-diethyl-1-(((1-(4-methylphenyl)butyl)amino)carbonyl)-4-oxo-2-azetidinyl)oxy)benzoate, Compound 10.

A.

To a solution of 1.0 gm [S-(R*,S*)]4-((3,3-diethyl-1-(((1-(4-methylphenyl)butyl)amino)carbonyl)-4-oxo-2-azetidinyl)oxy)benzoic acid in 10 ml methylene chloride is added 2 ml of oxalyl chloride followed by a catalytic amount of DMF. The reaction is stirred 1 hour at room temperature then concentrated in vacuo to yield the acid chloride which is used as is in the next step.

B.

A solution of the above acid chloride in 10 ml of methylene chloride is cooled in an ice bath and a solution of 1.25 gm benzyl L-lactate and 2.0 gm of triethylamine in 10 ml of methylene chloride is added. The mixture is stirred at room temperature overnight then concentrated in vacuo. Chromatography of the residue on silica gel using methylene chloride as the eluent yields 0.795 of the desired 1-Methyl-2-oxo-2-(phenylmethoxy)ethyl (2S-(1(S,),R*,(R)))-4-((3,3-diethyl-1-(((1-(4-methylphenyl)butyl)amino)carbonyl)-4-oxo-2-azetidinyl)oxy) benzoate, Compound 10.

Analysis: C₃₆ H₄₂ N₂ O₇ Calc: C, 70.34; H, 6.89; N, 4.56. Found: C, 70.45; H, 7.05; N, 4.48.

EXAMPLE 4

Preparation of 1-carboxyethyl[S-(R*,S*)]4-((3,3-diethyl-1-(((1-(4-methyl-phenyl)butyl)amino)carbonyl)-4-oxo-2-azetidinyl)oxy)benzoate

A mixture of 0.69 gm of the benzylester prepared in Example 3 and 0.2 gm 10% Pd/C in 10 ml of EtOAc is treated with hydrogen at 40 psi. When the reaction is complete the mixture is filtered and concentrated in vacuo to yield 0.56 gm of 1-carboxyethyl [S-(R*,S*)]4-((3,3-diethyl-1-(((1-(4-methylphenyl)butyl)amino)carbonyl)-4-oxo-2-azetidinyl)oxy) benzoate, Compound 11.

Analysis: C₂₉ H₃₆ N₂ O₇ Calc: C, 66.40; H, 6.92; N, 5.34. Found: C, 66.66; H, 7.26; N, 5.05.

EXAMPLE 5

2-(diethylamino)-1-methyl-2-oxoethyl[S-(R*,S*)]-4-((3,3-diethyl-1-(((1-(4-methyl-phenyl)butyl)amino)carbonyl)-4-oxo-2-azetidinyl)oxy) benzoate

The acid (0.250 gm) from Example 4 is treated with oxalyl chloride according to the procedure of Example 3A and the corresponding acid chloride is obtained. This material is dissolved in 5 ml methylene chloride and 0.4 ml of diethylamine added. After 1 hour the reaction mixture is concentrated in vacuo and the residue taken in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer is dried through sodium sulfate, concentrated and the residue chromatographed on silica gel. Elution with 5% of ethyl acetate methylene chloride gives Compound 12.

Analysis: C₃₃ H₄₅ N₃ O₆ Calc: C, 68.37; H, 7.82, N, 7.25 Found: C, 68.40; H, 7.93, N, 7.40.

EXAMPLE 6

(S(R*,S*))-1-(((4-((3,3-diethyl-1-(((1-(4-methylphenyl)butyl)amino)carbonyl)-4-oxo-2-azetidinyl)oxy)benzoyl)oxy)acetyl) L-proline,

A.

When benzyl L-lactate is replaced by L-proline benzyl ester hydrochloride and triethylamine in the procedure of Example 3 the corresponding amide with L-proline benzyl ester, Compound 8, is obtained.

Analysis: C₄₀ H₄₇ N₃ O₈ Calc: C, 68.85; H, 6.79, N, 6.02 Found: C, 68.79; H, 7.06, N, 5.88.

B.

Reduction of the material obtained in Example 6A according to the procedure of Example 4 affords Compound 9.

Analysis: C₃₃ H₄₁ N₃ O₈ +0.5H₂ O Calc: C, 64.27; H, 6.86; N, 6.81. Found: C, 64.49; H, 6.90; N, 6.68.

EXAMPLE 7

[S-(R*,S*)]1-(((4-((3,3-diethyl-1-(((1-(4-methylphenyl)butyl)amino) carbonyl-4-oxo-2-azetidinyl)oxy)benzoyl)oxy)acetyl-N-benzyl-L-prolinamide.

Treatment of the acid obtained in Example 6B, Compound 9, with oxalyl chloride according to Example 3A gives the corresponding acid chloride which when treated with benzylamine gives the desired benzyl amide, Compound 19.

Analysis: C₄₀ H₄₈ N₄ O₇ Calc: C, 68.95; H, 6.94; N, 8.04. Found: C, 68.93, H, 7.02; N, 7.96.

EXAMPLE 8

To a solution of the acid chloride (prepared from 0.55 gm of [S-(R*,S*)]4-((3,3-diethyl-1-(((1-(4-methylphenyl)butyl)amino)carbonyl)-4-oxo-2-azetidinyl)oxy)benzoic acid according to the procedure of Example 3A) in 3 ml of methylene chloride is added 0.15 gm of N,N-dimethylaminoethanol. The reaction mixture is stirred overnight at room temperature, concentrated in vacuo, then taken up in ethyl acetate (25 ml) and washed with saturated sodium bicarbonate solution. The organic layer is dried through sodium sulfate and concentrated in vacuo. Silica gel chromatography of the residue using 2.5% methanol in methylene chloride gives 0.59 gm of Compound 1, 2-(dimethylamino)ethyl(S-(R*,S*))-4-((3,3-diethyl-1-(((1-(4-methyl-phenyl)butyl)amino)carbonyl)-4-oxo-2-azetidinyl)oxy)benzoate

Analysis: C₃₀ H₄₁ N₃ O₅ Calc: C, 68.81; H, 7.89; N, 8.02. Found: C, 68.85; H, 8.09; N, 7.97.

When N,N-dimethylaminoethanolamine is replaced by the appropriate amino alcohols the corresponding esters are obtained.

Compound 13

1-Dimethylamino-2-propyl[S-(R*,S*)]-4-[[3,3-diethyl-1-[[[1-(4-methyl-phenyl)butyl]amino]carbonyl]-4-oxo-2-azetidinyl]oxy]benzoate

Analysis: C₃₁ H₄₃ N₃ O₅ Calc: C, 69.25; H, 8.06; N, 7.82. Found: C, 68.97; H, 8.01; N, 7.80.

Compound 14

3-Dimethylamino-1-propyl[S-(R*,S,)]-4-[[3,3-diethyl-1-[[[1-(4-methyl-phenyl)butyl]amino]carbonyl]-4-oxo-2-azetidinyl]oxy]benzoate

Analysis: C₃₁ H₄₃ N₃ O₅ Calc: C, 69.25; H, 8.06; N, 7.81. Found: C, 68.85; H, 8.19; N, 7.72.

Compound 16

2-Diethylaminoethyl [S-(R*,S*)]-4-[[3,3-diethyl-1-[[[1-(4-methyl-phenyl)butyl]amino]carbonyl]-4-oxo-2-azetidinyl]oxy]benzoate

Analysis: C₃₂ H₄₅ N₃ O₆ Calc: C, 69.66; H, 8.22; N, 7.62. Found: C, 69.37; H, 8.41; N, 7.51.

Compound 17

2-(1-[4-morpholino]ethyl) [S-(R*,S*)]-4-[[3,3-diethyl-1-[[[1-(4-methyl-phenyl)butyl]amino]carbonyl]-4-oxo-2-azetidinyl]oxy]benzoate

Analysis: C₃₂ H₄₃ N₃ O₆ Calc: C, 67.94; H, 7.66; N, 7.43. Found: C, 67.67; H, 7.90; N, 7.26.

Compound 18

4-dimethylaminobutyl [S-(R*,S*)]-4-[[3,3-diethyl-1-[[[1-(4-methyl-phenyl)butyl]amino]carbonyl]-4-oxo-2-azetidinyl]oxy]benzoate

Analysis: C₃₂ H₄₅ N₃ O₅ +0.2H₂ O Calc: C, 69.21; H, 8.24; N, 7.56. Found: C. 69.35; H, 8.24; N, 7.29.

Compound 20

2-dimethylamino-2-methyl-1-propyl [S-(R*,S*)]-4-[[3,3-diethyl-1-[[[1-(4-methyl-phenyl)butyl]amino]carbonyl]-4-oxo-2-azetidinyl]oxy]benzoate

Analysis: C₃₂ H₄₅ N₃ O₅ Calc: C, 69.66; H, 8.22; N, 7.62. Found: C, 69.52; H, 8.47; N, 7.59.

Compound 21

2-(diisopropylamino)ethyl [S-(R*,S*)]-4-[[3,3-diethyl-1-[[[1-(4-methyl-phenyl)butyl]amino]carbonyl]-4-oxo-2-azetidinyl]oxy]benzoate

Analysis: C₃₄ H₄₉ N₃ O₅ Calc: C, 70.44; H, 8.52; N, 7.25. Found: C, 70.28;. H, 8.76; N, 7.13.

Compound 22

Benzyl[S-(R*,S*)]-4-[2-[[4-[[3,3-diethyl-1-[[[1-(4-methylphenyl)butyl]amino]carbonyl]-4-oxo-2-azetidinyl]oxy]benzoyl]oxy]-ethyl]-1-Piperazinecarboxylate

Analysis: C₄₀ H₅₀ N₄ O₇ Calc: C, 68.75; H, 7.21; N, 8.02. Found: C, 68.39; H, 7.30; N, 7.84.

Compound 23

2-(dibutylamino)ethyl[S-(R*,S*)]-4-[[3,3-diethyl-1-[[[1-(4-methyl-phenyl)butyl]amino]carbonyl]-4-oxo-2-azetidinyl]oxy]benzoate, yl]oxy]benzoate,

Analysis: C₃₆ H₅₃ N₃ O₅ Calc: C, 71.14; H, 8.79; N, 6.91. Found: C, 71.00; H, 9.03; N, 6.81.

Compound 24

[S-(R*,S*)]-6-(dimethylamino)hexyl-4-[[3,3-diethyl-1-[[[1-(4-methyl-phenyl)butyl]amino]carbonyl]-4-oxo-2-azetidinyl]oxy]-benzoate

Analysis: C₃₄ H₄₉ N₃ O₅ +1H₂ O Calc: C, 68.31; H, 8.60; N, 7.03. Found: C, 68.34; H, 8.29; N, 6.86.

Compound 26

2-(4-methyl-1-piperazinyl)ethyl[S-(R*,S*)]-4-[[3,3-diethyl-1-[[[1-(4-methyl-phenyl)butyl]amino]carbonyl]-4-oxo-2-azetidinyl]oxy]benzoate,

Analysis: C₃₃ H₄₆ N₄ O₅ +0.8H₂ O Calc: C, 66.82; H, 8.09; N, 9.44. Found: C, 67.28; H, 8.10; N, 8.96.

Compound 28

2-(diphenylamino)ethyl[S-(R*,S*)]-4-[[3,3-diethyl-1-[[[1-(4-methylphenyl)butyl]amino]carbonyl]-4-oxo-2-azetidinyl]oxy]benzoate,

Analysis: C₄₀ H₄₅ N₃ O₅ +1.4H₂ O Calc: C, 71.40; H, 7.16; N, 6.25. Found: C, 71.62; H, 6.99; N, 5.99.

Compound 29

2-(di-2-propenylamino)ethyl [S-(R*,S*)]-4-[[3,3-diethyl-1-[[[1-(4-methylphenyl)butyl]amino]carbonyl]-4-oxo-2-azetidinyl]oxy]benzoate,

Analysis: C₃₄ H₄₅ N₃ O₅ Calc: C, 70.93; H, 7.88; N, 7.30. Found: C, 71.18; H, 8.06; N, 7.34.

Compound 30

2-(dimethylamino)-2-phenylethyl[S-(R*,S*)]-4-[[3,3-diethyl-1-[[[1-(4-methylphenyl)butyl]amino]carbonyl]-4-oxo-2-azetidinyl]oxy]benzoate,

Analysis: C₃₆ H₄₅ N₃ O₅ Calc. C, 72.09; H, 7.56; N, 7.00. Found: C, 71.75; H, 7.67; N, 6.70.

Compound 31

2-[methyl(phenylmethyl)amino]ethyl [S-(R*,S*)]-4-[[3,3-diethyl-1-[[[1-(4-methyl-phenyl )butyl]amino]carbonyl]-4-oxo-2-azetidinyl]oxy]benzoate,

When [S-(R*,S*)]-4-[[3,3-diethyl-1-[[[1-(4-methylphenyl) butyl]amino]carbonyl]-4-oxo-2-azetidinyl]oxy]-2,6-dimethyl benzoic acid is used in place of [S(R*,S*)]-4-[[3,3-diethyl-1-[[[1-(4-methylphenyl)butyl]amino]carbonyl]-4-oxo-2-azetidinyl]oxy]benzoic acid in the procedure of Example 3A and allowed to react with the appropriate amino alcohols the following esters are obtained.

Compound 304

2-(dimethylamino)ethyl [S,(R*,S*)]-4-[[3,3-diethyl-1-[[[1-(4-methylphenyl)butyl]amino]carbonyl]-4-oxo-2-azetidinyl]oxy]-2,6-dimethyl-benzoate,

Compound 305

2-(diethylamino)ethyl [S-(R*,S*)]-4-[[3,3-diethyl-1-[[[1-(4-methylphenyl)butyl]amino]carbonyl]-4-oxo-2-azetidinyl]oxy]-2,6-dimethyl-benzoate,

Compound 306

2-[bis(1-methylethyl)amino]-ethyl [S-(R*,S*)]-4-[[3,3-diethyl-1-[[[1-(4-methylphenyl)butyl]amino]carbonyl]-4-oxo-2-azetidinyl]oxy]-2,6-dimethylbenzoate.

Treatment of the acid [S-(R*,S*)]-4-[[3,3-diethyl-1-[[[1-(4-methylphenyl)butyl]amino]carbonyl]-4-oxo-2-azetidinyl]oxy]benzeneacetic acid with oxalyl chloride according to the procedure of Example 3A affords the corresponding acid chloride which when allowed to react with the appropriate amino alcohol according to the procedure of Example 8 gives the following amino esters:

Compound 32

Analysis: C₃₁ H₄₃ N₃ O₅ Calc: C, 69.25; H, 8.06; N, 7.82. Found: C, 69.02; H, 7.86; N, 7.74.

Compound 33

Analysis: C₃₂ H₄₅ N₃ O₅ Calc: C, 69.66; H, 8.22; N, 7.62. Found: C, 69.10; H, 8.17; N, 7.50.

Compound 34

Analysis: C₃₃ H₄₇ N₃ O₅ Calc: C, 70.06; H, 8.38; N, 7.43. Found: C, 69.70; H, 8.41; N, 7.05.

Compound 35

Analysis: C₃₃ H₄₅ N₃ O₆ Calc: C, 68.37; H, 7.82; N, 7.25. Found: C, 68.55; H, 8.19; 7.08.

Compound 36

Analysis: C₃₂ H₄₅ N₃ O₅ Calc: C, 69.66; H, 8.22; N, 7.62. Found: C, 69.60; H, 8.49; N 7.55.

EXAMPLE 9

To a solution of 0.247 g of Compound 1 in 2 ml of ethyl acetate is added 0.125 gm of m-chloroperoxy benzoic acid. After 30 minutes at room temperature the reaction mixture is concentrated in vacuo. Chromatography of the residue on silica gel using methylene chloride/methanol/water 85/15/1.5 gives the desired N-oxide Compound 15.

Analysis: C₃₀ H₄₁ N₃ O₈ +1.4H₂ O Calc: 63.79; H, 7.82; N, 7.44 Found: 63.89; H, 7.85; N, 7.27

EXAMPLE 10

[S-(R*,S*)]2-[4-[[[2-(dimethylamino)-ethyl]amino]carbonyl]phenoxy]-3,3-diethyl-N-[1-(4-methylphenyl)butyl]-4-oxo-1-azetidinecarboxamide.

To a solution of 0.104 g carbonyldiimidazole in 2 ml methylene chloride is added a solution of 0.227 g of [S-(R*,S*)]-4-((3,3-diethyl-1-((-1-(4-methylphenyl)butylamino)carbonyl)-4-oxo-2-azetidinyl)oxy)benzoic acid in 3 ml methylene chloride. The mixture is stirred at ambient temperature for 30 minutes at which time 0.100 g of N,N-dimethylethylenediamine is added. After Stirring overnight at room temperature the reaction mixture is poured into benzene (50 ml) and washed with water. The organic layer is separated, dried through sodium sulfate and concentrated in vacuo. Silica gel chromatography using 5% methanol in methylene chloride yields 0.160 g of 2-[4-[[[2-(dimethylamino)ethyl]carbonyl]phenoxy]-3,3-diethyl-N-[1-(4-methylphenyl)butyl]-4-oxo-1azetidinecarboxamide. (Compound 73).

Analysis: C₃₀ H₄₂ N₄ O₄ +0.4H₂ O Calc: C, 68.00; H, 8.14; N, 10.57. Found: C, 68.01; H, 8.18; N, 10.62.

EXAMPLE 11

A. (S-(R*,S*))-4-((3,3-diethyl-1-((1-(4-methylphenyl)butylamino)carbonyl)-4-phenyl)butylamino)carbonyl)-4-oxo-2-azetidinyl)oxy)-benzoyl chloride.

To a solution of 0.150 g of [S-(R*,S,)]4-((3,3-diethyl-1-(((1-(4-methylphenyl)butyl)amino)carbonyl)-4-oxo-2-azetidinyl)oxy)benzoic acid in 5 ml methylene chloride containing a catalytic amount of dimethylformamide is added 0.5 ml of oxalyl chloride. The mixture is stirred at room temperature for 30 minutes and then concentrated in vacuo to yield (S-(R*,S*))-4-((3,3-diethyl-1-((1-(4-methyl-phenyl)butylamino(carbonyl)-4-oxo-2-azetidinyl)oxy)-benzoyl chloride.

B. [S-(R*,S*)]-2-[4-[[[2-(dimethylamino)ethyl]methylamino]carbonyl]-phenoxy]-3,3-diethyl-N-[1-(4-methylphenyl]butyl]-4-oxo-1-azetidinecarboxamide.

The above acid chloride is dissolved in 3 ml methylene chloride and a solution of 0.20 gm of N,N,N'-trimethylethylenediamine in 2 ml methylene chloride is added. The mixture is stirred overnight and then concentrated in vacuo. The residue is extracted between ethyl acetate and saturated sodium bicarbonate solution. The organic layer is dried through sodium sulfate and concentrated in vacuo. Silica gel chromatography of the residue (5% methanol in methylene chloride) affords 0.117 g of [S-(R*,S*)]-2-[4-[[[2-(dimethylamino)ethyl]methylamino]carbonyl]-phenoxy]phenoxy]-3,3-diethyl-N-[1-(4-methylphenyl]butyl]-4-oxo-1-azetidinecarboxamide. (Compound 75).

Analysis: C₃₁ H₄₄ N₄ O₄ +0.5H₂ O Calc: C, 68.23; H, 8.31; N, 10.27. Found: C, 68.20; H, 8.41; N, 10.10.

When N,N,N'-trimethylethylenediamine of Example 11b is replaced by the appropriate amines, there is obtained the corresponding amides.

1) Compound 76

Analysis: C₃₂ H₄₆ N₄ O₄ Calc: C, 69.79; H, 8.42; N, 10.17. Found: C, 69.02; H, 8.60; N, 9.54.

2) Compound 77

Analysis: C₃₂ H₄₆ N₄ O₄ +0.75 H₂ O Calc: C, 68.12; H, 8.49; N, 9.93. Found: C, 68.22; H, 8.48; N, 10.17.

3) Compound 78

Analysis: C₃₂ H₄₄ N₄ O₅ Calc. C, 68.06; H, 7.85; N, 9.92. Found: C, 67.84; H, 8,07; N, 9.62.

4) Compound 79

Analysis: C₃₃ H₄₆ N₄ O₅ +H₂ O Calc: C, 66.42; H, 8.11; N, 9.39. Found: C, 66.73; H, 8.19; N, 9.23.

5) Compound 80

Analysis: C₃₅ H₅₂ N₄ O₆ Calc: C, 67.28; H, 8.39; N, 8.97. Found: C, 67.08; H, 8.77; 8.41.

6) Compound 81

Analysis: C₃₃ H₄₈ N₄ O₄ +H₂ O Calc: C, 68.01; H, 8.65; N, 9.61. Found: C, 68.42; H, 8.59; N, 9.17.

7) Compound 82

Analysis: C₃₆ H₄₆ N₄ O₄ +0.5H₂ O Calc: C, 71.14; H, 7.79; N, 9.21. Found: C, 71.41; H, 7.68; N, 9.10.

8) Compound 83

Analysis: C₃₂ H₄₆ N₄ O₄ +1.2H₂ O Calc: C, 67.15; H, 8.52; N, 9.79. Found: C, 67.21; H, 8.26; N, 9.47.

9) Compound 84

10) Compound 86

Analysis: C₃₅ H₅₂ N₄ O₄ Calc: C, 70.91; H, 8.84; N, 9.45. Found: C, 70.37; H, 8.84; N, 8.77.

11) Compound 89

Analysis: C₃₁ H₃₉ N₅ O₄ +0.7H₂ O Calc: C, 66.71; H, 7.29; N, 12.54. Found: C, 66.91; H, 7.40; N, 12.14.

12) Compound 90

Analysis: C₃₃ H₄₆ N₄ O₄ +0.8H₂ O Calc: C, 68.67; H, 8.31; N, 9.70. Found: C, 68.82; H, 8.11; N, 9.70.

13) Compound 91

Analysis: C₃₄ H₄₈ N₄ O₄ +0.3H₂ O Calc: C, 70.11; H, 8.41; N, 9.61. Found: C, 70.17; H, 8.64; N, 9.33.

14) Compound 92

Analysis: C₃₀ H₄₂ N₄ O₄ +1.2H₂ O Calc: C, 66.14; H, 8.22; N, 10.29. Found: C, 66.18; H, 8.12; N, 10.31.

15) Compound 93

Analysis: C₃₂ H₄₄ N₄ O₆ +0.3H₂ O Calc: C, 65.57; H, 7.67; N, 9.56. Found: C, 65.72; H, 7.50; N, 9.34.

16) Compound 94

Analysis: C₃₂ H₄₄ N₄ O₄ +0.3H₂ O Calc: C, 70.04; H, 8.08; N, 10.21. Found: C, 70.34; H, 8.90; N, 8.93.

17) Compound 95

Analysis: C₃₃ H₄₆ N₄ O₄ +0.5H₂ O Calc: C, 69.32; H, 8 28; N, 9.80. Found: C, 69.41; H, 8.25; N, 9.58.

18) Compound 99

Analysis: C₃₈ H₅₄ N₄ O₄ +1.5H₂ O Calc: C, 69.37; H, 8.72; N, 8.51 Found: C, 69.48; H, 8.44; N, 8.36

19) Compound 102

Analysis: C₄₀ H₄₉ N₅ O₆ +1.0H₂ O Calc: C, 67.30; H, 7.20; N, 9.81 Found: C, 67.50; H, 7.24; N, 9.53

20) Compound 104

Analysis: C₃₂ H₄₁ N₅ O₄ +0.75H₂ O Calc: C, 67.04; H, 7.47; N, 12.21. Found: C, 67.16; H, 7.56; N, 11.95.

21) Compound 105

Analysis: C₃₂ H₄₄ N₄ O₅ +0.5H₂ O Calc: C, 66.99; H, 7.91; N, 9.77. Found: C, 67,00; H, 8.25; N, 9.50.

Compound 106

Analysis: C₃₂ H₄₅ N₅ O₅ +0.8H₂ O Calc: C, 64.69; H, 7.90; N, 11.78. Found: C, 64.93; H, 8.25; N, 11.12.

23) Compound 107

Analysis: C₃₁ H₄₄ N₃ O₆ S+0.3H₂ O Calc: C, 61.42; H, 7.41; N, 9.24. Found: C, 61.43; H, 7.54; N, 9.05.

24) Compound 110

Analysis: C₃₅ H₄₄ N₄ O₄ Calc: C, 71.89; H, 7.58; N, 9.58. Found: C, 71.65; H, 7.55; N, 9.34.

25) Compound 111

Analysis: C₃₄ H₄₂ N₄ O₄ +0.5H₂ O Calc: C, 70.44; H, 7.47, N, 9.66. Found: C, 70.82, H, 7.46; N, 9.20.

26) Compound 113

Analysis: C₃₄ H₄₂ N₄ O₄ +0.3H₂ O Calc: C, 70.88; H, 7.45; N, 9.72. Found: C, 71.12; H, 7.44; N, 9.32.

27) Compound 115

Analysis: C₃₄ H₄₂ N₄ O₄ +0.7H₂ O Calc: C, 69.99; H, 7.50; N, 9.60. Found: C, 70.14, H, 7.63; N, 9.25.

28) Compound 116

Analysis: C₃₄ H₄₆ N₄ O₄ +1.4H₂ O Calc: C, 68.06; H, 8.19; N, 9.33. Found: C, 68.40; H, 8.14; N, 8.87.

29) Compound 117

Analysis: C₄₀ H₅₁ N₅ O₆ +0.6H₂ O Calc: C, 67.79; H, 7.42; N, 9.88. Found: C, 67.81; H, 7.58; N, 9.76.

30) Compound 118

Analysis: C₃₃ H₄₇ N₅ O₄ +0.7H₂ O Calc: C, 67.14; H, 8.26; N, 11.86 Found: C, 67.54; H, 8.51; N, 11.28.

31) Compound 119

Analysis: C₃₅ H₄₈ N₄ O₄ +1.25H₂ O Calc: C, 68.76; H, 8.32; N, 9.16. Found: C, 69.07; H, 8.19; N, 8.75.

32) Compound 121

Analysis: C₃₄ H₄₈ N₄ O₄ +1H₂ O Calc: C, 68.66; H, 8.47; N, 9.42. Found: C, 69.02; H, 8.32; N, 9.06.

33) Compound 125

Analysis: C₃₇ H₄₈ N₄ O₄ +0.5H₂ O Calc: C, 71.47; H, 7.94; N, 9.01 Found: C, 71.65; H, 7.91; N, 8.73.

34) Compound 126

Analysis: C₄₁ H₅₄ N₄ O₅ +2H₂ O Calc: C, 68.83; H, 8.25; N, 7.64. Found: C, 69.03; H, 7.79; N, 7.50.

35) Compound 132

Analysis: C₃₅ H₅₀ N₄ O₄ Calc: C, 71.15; H, 8.53; N, 9.48. Found: C, 70.90; H, 8.74; 9.12.

36) Compound 133

Analysis: C₄₀ H₅₂ N₄ O₄ +0.9H₂ O Calc: C, 71.80; H, 8.10; N, 8.37. Found: C, 71.86; H, 8.17; N, 8.18.

37) Compound 137

Analysis: C₃₇ H₄₈ N₄ O₄ +0.8H₂ O Calc. C, 70.85; H, 7.97; H, 8.93. Found: C, 71.01; H, 7.97; N, 8.54.

38) Compound 139

Analysis: C₃₉ H₅₁ N₅ O₄ +0.8H₂ O Calc: C, 70.09; H, 7.93; N, 10.48. Found: C, 70.18; H, 7.79; N, 10.42.

39) Compound 142

Analysis: C₃₈ H₅₅ N₅ O₆ Calc: C, 67.33; H, 8.18; N, 10.33. Found: C, 67.02; H, 8.31; N, 9.89.

40) Compound 143

Analysis: C₃₄ H₅₁ N₅ O₄ Calc: C, 68.77; H, 8.66; N, 11.80. Found: C, 68.57; H, 8.50; N, 11.53

41) Compound 144

Analysis: C₃₈ H₅₉ N₅ O₄ +0.4H₂ O Calc: C, 69.45; H, 9.17; N, 10.65. Found: C, 69.69; H, 9.02; N, 10 35.

42) Compound 145

Analysis: C₃₆ H₄₇ N₅ O₄ +H₂ O Calc: C, 68.44; H, 7.82; N, 11.08 Found: C, 68.69; H, 7.74; N, 10.76.

43) Compound 148

Analysis: C₃₆ H₄₇ N₅ O₄ +0.4H₂ O Calc: C, 69.62; H, 7.56; N, 11.27. Found: C, 69.79; H, 7.70; N, 11.12.

44) Compound 149

Analysis: C₃₉ H₅₀ N₄ O₄ +0.4H₂ O Calc: C, 72.50; H, 7.93; N, 8.67 Found: C, 72.44; H, 7.99; N, 8.87.

45) Compound 150

Analysis: C₃₆ H₄₇ N₅ O₄ +0.3H₂ O Calc. C, 69.83; H, 7.74; N, 11.31. Found: C, 69.93; H, 7.65, N, 11.10.

46) Compound 151

Analysis: C₃₃ H₄₇ N₅ O₄ Calc: C, 68.60; H, 8.20; N, 12.12. Found: C, 68.40; H, 8.16; N, 11.90.

47) Compound 245

Analysis: C₃₆ H₄₄ N₄ O₄ Calc: C, 72.46; H, 7.43; N, 9.39 Found: C, 72.49; H, 7.49; N, 9.25

48) Compound 246

Analysis: C₃₇ H₄₆ N₄ O₄ +0.25H₂ O Calc: C, 72.26; H, 7.61; N, 9.10. Found: C, 72.35; H, 7.83; N, 8.73.

49) Compound 154

Analysis: C₃₅ H₄₈ N₄ O₄ +0.8H₂ O Calc: C, 69.70; H, 8.29; N, 9.29 Found: C, 69.65; H, 8.27; N, 9.35.

50) Compound 158

Analysis: C₃₅ H₄₈ N₄ O₄ +0.5H₂ O Calc: C, 73.29; H, 7.65; N, 8.33. Found: C, 73.71, H, 7.75, N, 7.75.

51) Compound 159

Analysis: C₃₅ H₄₈ N₄ O₄ Calc: C, 73.09; H, 7.66; N, 8.31. Found: C, 73.40; H, 7.75; N, 7.80.

52) Compound 160

Analysis: C₃₈ H₄₈ N₄ O₄ +1.0H₂ O Calc: C, 70.78; H, 8.12; N, 8.68. Found: C, 71.00; H, 8.05; N, 8.59.

53) Compound 161

Analysis: C₄₃ H₅₂ N₄ O₄ +1H₂ O Calc: C, 73.05; H, 7.70; N, 7.92. Found: C, 73.29; H, 7.95; N, 7.37.

54) Compound 166

Analysis: C₃₃ H₄₆ N₄ O₄ +1.5H₂ O Calc. C, 67.20; H, 8.37; N, 9.50 Found: C, 67.38; H, 7.98; N, 9.41.

55) Compound 171

Analysis: C₃₆ H₅₂ N₄ O₆ +1.6H₂ O Calc: C, 64.95; H, 8.36; N, 8.41. Found: C, 65 26; H, 8.15; N, 8.07.

56) Compound 177

Analysis: C₃₈ H₄₇ N₅ O₄ Calc: C, 71.56; H, 7.43; N, 10,98. Found: C, 71 64; H, 7.62; 10.93.

57) Compound 178

Analysis: C₃₈ H₅₀ N₄ O₄ Calc: C, 72.81; H, 8.04; N, 8.94. Found: C, 72.96;H, 8.17;N, 8.83.

58) Compound 179

Analysis: C₃₈ H₄₇ N₅ O₄ Calc: C, 71.56; H, 7.43; N, 10.98. Found: C, 72.00; H, 7.55;N 10.87.

59) Compound 180

Analysis: C₃₈ H₄₇ F₃ N₄ O₄ Calc: C, 67.04; H, 6.96; N, 8.23. Found: C, 67.02; H, 7.25;N, 8.23.

60) Compound 181

Analysis: C₃₈ H₄₇ F₃ N₄ O₄ Calc: C, 67.04; H, 6.96; N, 8.23 Found: C, 66.63; H, 6.98; N, 7.94.

61) Compound 182

Analysis: C₃₇ H₄₇ F N₄ O₄ Calc: C, 70.45; H, 7.51; N, 8.88 Found: C, 70.28; H, 7.74;N, 8.82.

62) Compound 185

Analysis: C₃₄ H₄₈ N₄ O₄ Calc: C, 70.80; H, 8.39; N, 9.71 Found: C, 70.44; H, 8.45; N, 9.51.

63) Compound 186

Analysis: C₃₇ H₄₈ N₄ O₄ +0.8H₂ O Calc: C, 70.85; H, 7.97; N, 8.93 Found: C, 71.12; H, 8.25; N, 8.45.

64) Compound 191

Analysis: C₄₂ H₅₁ N₅ O₄ +0.5CH₂ Cl₂ Calc: C, 69.78; H, 7.16; N, 9.58 Found: C, 69.75; H, 7.31; N, 9.68.

65) Compound 203

Analysis: C₃₇ H₄₇ N₄ O₄ +1.1H₂ O Calc: C, 68.31; H, 7.62; N, 8.61 Found: C, 68.32; H, 7.57; N, 8.53.

66) Compound 204

Analysis: C₃₇ H₄₇ ClN₄ O₄ Calc: C, 68.66; H, 7.32; N, 8.66. Found: C, 68.32, H, 7.48; N, 8.42.

67) Compound 205

Analysis: C₃₈ H₅₀ N₄ O₅ +0.7H₂ O Calc: C, 69.63; H, 7.90; N, 8.54. Found: C, 69.72; N, 7.91; N, 8.54.

68) Compound 206

Analysis: C₃₉ H₅₂ N₄ O₆ +0.8H₂ O Calc: C, 68.15; H, 7.86; N, 8.15 Found: C, 68.01; H, 8.02; N, 8.15.

EXAMPLE 12

A) [S-(R*,S*)]3,3-Diethyl-2-[4-[[[2-(4-hydroxy-1-piperidinyl)ethyl]amino]carbonyl]phenoxy]-N-[1-(4-methylphenyl)butyl]-4-oxo-1-azetidinecarboxamide

When 1-(2-aminoethyl)-4-benzyloxypiperidine is used in place of N,N,N'-trimethylethylene diamine in the procedure of Example 11b there is obtained [S-(R*,S*)]3,3-diethyl-2-[4-[[[2-(4-benzyloxy-1-piperidinyl]ethyl]amino]carbonyl]phenoxy]-N-[1-(4-methylphenyl)butyl]-4-oxo-1-azetidinecarboxamide.

B) [S-(R+,S*)]-3,3-diethyl-2-[4-[[[2-(4-hydroxy-1-piperidinyl)ethyl]amino]carbonyl ]phenoxy]-N-[1-(4-methyl-phenyl)butyl]-4-oxo-1-azetidine-carboxamide

A solution of the amide from step A above in 10 ml of glacial acetic acid containing 22 mg of 10% Pd/C is hydrogenated under 42 lb hydrogen pressure. When TLC-indicate completion of the reaction, the mixture is filtered and concentrated in vacuo after the addition of 50 ml toluene. The residue is dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution. The organic layer is dried with sodium sulfate and concentrated in vacuo. The residue is chromatographed on 15 g silica gel using 5% methanol in methylene chloride and yields 96 mg of

[S-(R+,S*)]-3,3-diethyl-2-[4-[[[2-(4-hydroxy-1-piperidinyl)ethyl]amino]carbonyl]phenoxy]-N-[1-(4-methyl-phenyl)butyl]-4-oxo-1-azetidine-carboxamide

Analysis: C₃₃ H₄₆ N₄ O₅ +1.3H₂ O Calc: C, 65.83; H, 8.13; N, 9.30 Found: C, 66.10; H, 8.06; N, 8.91

When 1-(2-aminoethyl )-4-benzyloxypiperidine is replaced in the procedure of Example 12 by the appropriate amines, the following compounds 123, 124, 129,131 and 138 are obtained, for example:

1) Compound 129

Analysis: C₃₄ H₄₈ N₄ O₅ Calc: C, 68.89; H, 8.16; N, 9.45 Found: C, 68.68; H, 8.18; N, 8.65

2) Compound 131

Analysis: C₃₂ H₄₄ N₄ O₅ +1H₂ O Calc: C, 65.92; H, 7.96; N, 9.61 Found: C, 66.07; H, 7.86; N, 9.45

3) Compound 138

Analysis: C₃₃ H₄₆ N₄ O₅ +0.5H₂ O Calc: C, 67.43; H, 8.06; N, 9.53 Found: C, 67.61; H, 8.06; N, 9.37

Diamine Intermediates

The diamines used to prepare the amino amides described herein were commercially available or prepared according to the following routes ##STR32##

EXAMPLE 13

A. N-cyanomethylhomopiperazine.

To a solution of 1.98 g homopiperazine in 50 ml acetone is added 4.25 g of powdered anhydrous sodium carbonate and 1.3 ml of chloroacetonitrite. After 24 hrs the reaction mixture is filtered and the filter cake washed with 100 ml acetone. The combined filtrates are concentrated in vacuo and the residue chromatographed on silica gel using methylene chloride as the eluent. The yield of N-cyanomethyl homopiperazine is 2.69 g.

B. N-(2-aminoethyl)homopiperazine.

To a suspension of 1.02 g lithium aluminum hydride in 50 ml of ether is slowly added a solution of 2.65 gm N-cyanomethyl homopiperazine in 25 ml ether. After the addition in complete the mixture is heated at reflux for 1 hour, then cooled to room temperature and quenched carefully with 1 ml water, 1 ml of 15% sodium hydroxide solution and 3 ml water. The mixture is filtered through sodium sulfate, the filter cake washed well with ether and the combined filtrates concentrated in Vacuo to yield 2.60 g. N-(2-aminoethyl)homopiperazine. ##STR33##

EXAMPLE 14 N-(2-methylaminoethyl)homopiperazine

A). N-(2-formamidoethyl)homopiperazine.

To a carefully prepared solution of 0.718 g of 60% sodium hydride dispension in 75 ml of absolute ethanol which has been cooled to 0° C. is added 7.3 ml of ethyl formate. After 5 minutes there is added a solution of 2.55 gm of N-(2-aminoethyl)homopiperazine in 25 ml absolute ethanol. The mixture is stirred at room temperature overnight. Saturated sodium bicarbonate solution (15 ml) is then added and the reaction mixture is stirred with 150 ml ethyl acetate, filtered through MgSO₄ and the filtrate concentrated in vacuo. Chromatography of the residue on 150 gm silica gel using an eluent of methylene chloride/methanol/conc. ammonium hydroxide (95/5/0.5) gives 2.78 g of N-(2-formamidoethyl)homopiperazine.

B). N-(2-methylaminoethyl)homopiperazine.

To a solution of 2.75 gm of N-(2-formamidoethyl)homopiperazine in 20 ml of dry THF under N₂ is added carefully 60 ml of borane THF solution. After the addition is complete the reaction mixture is heated to reflux for 5 hours then stirred at room temperature overnight. The reaction mixture is quenched by the careful addition of 20 ml of 6N HCl followed by refluxing for 1 hour. The reaction mixture is cooled, 50 ml of water added and solid KOH added carefully to alkaline pH. Extraction with ether gives the desired product N-(2-methylamino) homopiperazine.

EXAMPLE 15 ##STR34## A) N-benzyl-N,N'-dimethyl-N'-(2-phenylethyl)ethylenediamine

A mixture of 0.900 gm N-benzyl-N,N'-dimethylethylenediamine, 1.10 gm powdered sodium carbonate and 0.75 ml of 2-phenylethylbromide is refluxed for 5 hours. An additional 0.25 ml of bromide is added during this time. The reaction mixture is then cooled and filtered. The filterate is concentrated in vacuo and the residue chromatographed on silica gel using an eluent of CH₂ Cl₂ /CH₃ OH/NH₄ OH (97/3/0.3) to yield 0.875 gm of N-benzyl-N,N'-dimethyl-N'-(2-phenylethyl)ethylenediamine.

B) N,N'-dimethyl-N-(2-phenylethyl)ethylenediamine.

To a solution 0.870 gm N-benzyl-N-N'-dimethyl-N'-(2-phenylethyl)ethylenediamine in 10 ml ethanol and 5 ml acetic acid is added 0.18 gm Pd (OH)₂ /C. The mixture is hydrogenated at 40 psi for 3.5 hours, then filtered and concentrated in vacuo. The residue is made akaline with 1N NaOH and extracted well with ethyl acetate (5×25 ml). The combined extracts are filtered through sodium sulfate and concentrated to yield N,N'-dimethyl-N-(2-phenylethyl)ethylenediamine.

EXAMPLE 16 ##STR35## A)

A solution of 1.28 gm 1-(2-amino-ethyl)piperidine and 1.07 gm pyridine-3-carboxaldehyde in 40 ml of toluene is heated to reflux under a Dean Stark trap. After 10 ml toluene distilled over the NMR of an aliquot indicated no aldehyde left. The reaction mixture was concentrated and the imine used directly in the next step.

B)

To a suspension of 0.380 gm of lithium aluminum hydride in 30 ml of dry THF which has been cooled to -10° C. is added dropwise a solution of the above imine in 20 ml of dry THF. After about 1 hour the cold reaction mixture is quenched by the addition of 5 ml of 5N NaOH, then diluted with 100 ml ether and 20 ml of water. The organic layer is separated, washed with brine, filtered thru sodium sulfate and concentrated to give 2.17 gm of 1-[2-(3-pyridylmethylamino)ethyl]-piperidine suitable for use in subsequent reactions.

EXAMPLE 17 ##STR36##

To 7.50 gm of N,N'-dimethylethylenediamine which has been cooled in an ice-ethanol bath is added portionwise over a 30 minute period 1.40 gm of 3-picolyl chloride. After stirring cold for 1 hour after the addition is completed, the reaction mixture is concentrated in vacuo and the residue partitioned between 50 ml of ether and 10 ml of 5N NaOH solution. The organic layer is separated and the aqueous layer extracted 2 times with 50 ml of ether. The combined organic extracts are dried through sodium sulfate and concentrated in vacuo. Chromatography on 150 gm silica gel using CH₂ Cl₂ /CH₃ OH/NH₄ OH (90/10/1) as eluent gives 0.930 g of N,N'-dimethyl-N-(3-pyridylmethyl)ethylenediamine.

EXAMPLE 18

Amino Acid→diamine

A) To an ice cooled solution of 2.29 N-CBZ-D-Prolinein 50 ml of CHCl₂ is added 1.35 gm 1-hydroxybenzotriazole hydrate followed by 2.06 gm of dicyclohexylcarbodiimide. After 20 minutes, 0.85 ml of pyrrolidine is added and the reaction mixture stirred overnight after which time it is filtered and the filtrate concentrated in vacuo. The residue is partitioned between 100 ml ethyl acetate and 50 ml of 2N hydrochloric acid. The organic layer is separated, washed with 50 ml of 1.0N sodium hydroxide solution, dried through sodium sulfate and concentrated in vacuo. Chromatography on 150 gm of silica gel using ethylacetate in hexanes (30-100%) as eluent gives 2.04 gm of the desired pyrrolidine amide

B) To a solution of 1.519 gm of the amide (prepared in A) in 20 ml absolute ethanol is added 75 mg of 10% Pd on carbon catalyst. The mixture is hydrogenated at 40 psi for about an hour then filtrate and the filtrate concentrated to yield D-proline pyrrolidine amide.

C) To a suspension of 0.380 gm of lithium aluminum hydride in 15 ml of dry tetrahydrofuran is carefully added a solution of the D-proline amide (prepared in B above) in 10 ml tetrahydrofuran. The mixture is refluxed for 2 hrs then cooled and quenched with 2 ml of 2.5N sodium hydroxide. The mixture is filtered through a pad of sodium sulfate and the filter cake washed with 2×50 ml of ether. The combined filtrates are concentrated in vacuo to yield 0.80 gm of desired 2-(1-pyrrolidinylmethyl) pyrrolidine.

EXAMPLE 19

[S-(R*,S*)]-2-[4-[[(4-Methyl)piperazin-1-yl]carbonyl]phenoxy]((3,3-diethyl-N-[1-(methylphenyl)butyl]-4-oxo-1-azetidinecarboxamide

A solution of S-(R*,S*)]-4-(((3,3-diethyl-1-((4-methylphenyl)butylamino)carbonyl)-4-oxo-2-azetidinyl)oxy)benzoyl chloride (3.8 mmol), prepared as in Example 11A, in 50 ml of methylene chloride was cooled in an ice bath and a solution of 0.70 gm of N-methylpiperazine in 10 ml of methylene chloride was added over 5 min. The reaction was stirred for 1 hr and was then poured into a mixture of ice water and 10% potassium carbonate. The product was extracted with two portions of methylene chloride and each methylene chloride layer was washed with a portion of brine. The methylene chloride layers were combined, dried over sodium sulfate and evaporated. The residue was purified with flash chromatography using ethyl acetate, then 2% triethylamine/10% methanol/88% ethyl acetate to afford 2.1 gm of the title compound as a white solid.

Analysis: C₃₀ H₄₂ N₄ O₄ Calc: C, 69.64; H, 7.92; N, 10.48 Found: C, 69.62; H, 8.23; N, 10.46

EXAMPLE 20

[S-(R*,S*)]-2-[4-[[(4-Methyl)piperazin-1-yl]carbonyl]phenoxy]-((3,3-diethyl-N-[1-(3,4-methylenedioxyphenyl)butyl]-4-oxo-1-azetidinecarboxamide

When [S-(R*,S*)]-4-(((3,3-diethyl-1-((3,4-methylenedioxyphenyl)butylamino)carbonyl)-4-oxo-2-azetidinyl)oxy)benzoyl chloride (3.1 mmol), prepared as in Example 11A, was reacted with N-methylpiperazine as in Example 19, there was obtained 1.75 gm of the title compound.

Analysis: C₃₁ H₄₀ N₄ O₆ Calc: C, 65.94; H, 7.14; N, 9.92 Found: C, 65.80; H, 7.31; N, 10.05

EXAMPLE 21

[S-(R*,S*)]-2-[4-[[(4-Hydroxyethyl)piperazin-1-yl]carbonyl]phenoxy]-((3,3-diethyl-N-[1-(methylphenyl)butyl]-4-oxo-1-azetidinecarboxamide

When [S-(R*,S*)]-4-(((3,3-diethyl-1-((4-methylphenyl)butylamino)carbonyl)-4-oxo-2-azetidinyl)oxy)benzoyl chloride (3.8 mmol), prepared as in Example 11A, was reacted with N-(2-hydroxyethyl)piperazine (7.6 mmol) and diisopropylethylamine (3.8 mmol) as in Example 19, there was obtained 2.1 gm of the title compound.

Analysis: C₃₂ H₄₄ N₄ O₅ Calc: C, 68.06; H, 7.85; N, 9.92 Found: C, 67.88; H, 7.87; N, 10.17

EXAMPLE 22

[S-(R*,S*)]-2-[4-[[(4-Hydroxyethyl)piperazin-1-yl]carbonyl]phenoxy]-((3,3-diethyl-N-[1-(3,4-methylene dioxyphenyl)butyl]-4-oxo-1-azetidinecarboxamide

When [S-(R*,S*)]-4-(((3,3-diethyl-1-((3,4-methylenedioxyphenyl)butylamino)carbonyl)-4-oxo-2-azetidinyl)oxy)benzoyl chloride (3.1 mmol), prepared as in Example 11A, was reacted with N-(2-hydroxyethyl)piperazine (6.2 mmol) and diisopropylethylamine (3.1 mmol) as in Example 19, there was obtained 1.50 gm of the title compound.

Analysis: C₃₂ H₄₂ N₄ O₇.1.5H2O Calc: C, 61.94; H, 6.89; N, 9.06 Found: C, 61.95; H, 6.92; N, 8.96

EXAMPLE 23

[S-(R*,S*)]-2-[4-[[(4-Cyclopropyl)piperazin-1-yl]carbonyl]phenoxy]-((3,3-diethyl-N-[1-(4-methylphenyl)butyl]-4-oxo-1-azetidinecarboxamide

To a solution of [S-(R*,S*)]-4-(((3,3-diethyl-1-((4-methylphenyl)butylamino)carbonyl)-4-oxo-2-azetidinyl)oxy)benzoyl chloride (3.8 mmol), prepared as in Example 11A, in 50 ml of methylene chlorine was added N-(cyclopropyl)piperazine dihydrochloride (5.7 mmol) and then a solution of diisopropylethylamine (15.8 mmol) in 10 ml of methylene chloride was added over 5 min with ice-bath cooling. The reaction was stirred for 1 hr at 0 C and then poured into ice water. The product was extracted with two portions of methylene chloride and each methylene chloride layer was washed with a portion of brine. The methylene chloride layers were combined, dried over sodium sulfate and ethyl acetate/50% hexanes, then 70% ethyl acetate/30% hexanes to afford 2.1 gm of the title compound as a white solid.

Analysis: C₃₂ H₄₂ N₄ O₄ Calc: C, 70.69; H, 7.91; N, 9.99 Found: C, 70.62; H, 8.04; N, 9.95

EXAMPLE 24

[S-(R*,S*)]-2-[4-[[(4-Cyclopropyl)piperazin-1-yl]carbonyl]phenoxy]-((3,3-diethyl-N-[1-(3,4-methylene dioxyphenyl)butyl]-4-oxo-1-azetidinecarboxamide

When [S-(R*,S*)]-4-(((3,3-diethyl-1-((3,4-methylenedioxyphenyl)butylamino)carbonyl)-4-oxo-2-azetidinyl)oxy)benzoyl chloride (3.1 mmol), prepared as in Example 11A, was reacted with N-(cyclopropyl)piperazine (4.6 mmol) and diisopropylethylamine (9.3 mmol) as in Example 23, there was obtained 1.80 gm of the title compound.

Analysis: C₃₂ H₄₂ N₄ O₇ Calc: C, 67.10; H, 7.17; N, 9.49 Found: C, 67.03; H, 7.31; N, 9.47

EXAMPLE 25

[S-(R*,S*)]-2-[4-[[(4-Piperazin-1-yl)carbonyl]phenoxy]-((3,3-diethyl-N-[1-(4-methylphenyl)butyl]-4-oxo-1-azetidinecarboxamide

Step A: [S-R*,S*)]-2-[4-[[(4-(t-Butoxycarbonyl))piperpazin-1-yl]carbonyl]phenoxy]-((3,3-diethyl-N-[(4-methylphenyl)butyl]-4-oxo-1-azetidinecarboxamide

[S-(R*,S*)]-4-(((3,3-Diethyl-1-((4-methylphenyl)butylamino)carbonyl)-4-oxo-2-azetidinyl)oxy)benzoyl chloride (0.4 mmol), prepared as in Example 11A, was reacted with N-(t-butoxycarbonyl )piperazine (0.6 mmol) and triethylamine (1.2 mmol) as in Example 23. The crude, title product so obtained was used directly in the following Step B.

Step B: [S-R*,S*)]-2-[4-[(Piperazin-1-yl)carbonyl]phenoxy]-((3,3-diethyl-N-[1-(4-methylphenyl)butyl-4-oxo-1-azetidinecarboxamide

The product from Step A was dissolved in 0.5 ml anisole and 2 ml of cold TFA was added. The reaction was stirred at 0 C for 1 hr and was then diluted with methylene chloride and evaporated. The residue was taken up in methylene chloride, washed with 10% sodium carbonate and brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography using 5, then 10% methanol/methylene chloride to afford 0.212 gm of title product.

Analysis: C₃₀ H₄₀ N₄ O₅.1H₂ O Calc: C, 66.89; H, 7.85; N, 10.40 Found: C, 67.06; H, 7.55; N, 10.30

EXAMPLE 26 [S-(R*,S*)]-2-[4-[[(4-Piperazin-1-yl)carbonyl]phenoxy]-((3,3-diethyl-N-[1-(3,4-methylenedioxyphenyl)butyl]-4-oxo-1-azetidinecarboxamide

Step A: [S-R*,S*)]-2-[4-[[(4-Benzyloxycarbonyl) Piperazin-1-yl]carbonyl]phenoxy]-((3,3-diethyl-N-[1-3,4-methylenedioxyphenyl)butyl]-4-oxophenyl)butyl]-4-oxo-1-azetidinecarboxamide

When [S-(R*,S*)]-4-(((3,3-diethyl-1-((3,4-methylenedioxphenyl)butylamino)carbonyl)-4-oxo-2-azetidinyl)oxy)benzoyl chloride (0.41 mmol), prepared as in Example 11A, was reacted with N-(benzyloxycarbonyl)piperazine (0.77 mmol) and diisopropylethylamine (1.6 mmol) as in Example 23, there was obtained 290 mg of the title compound.

Step B. [S-R*,S*)]-2-[4-[(Piperazin-1-yl)carbonyl]phenoxy]-((3,3-diethyl-N-[1-(3,4-methylenedioxyphenyl)butyl-4-oxo-1-azetidinecarboxamide

A solution of 250 mg of material from Example 26, Step A in 10 ml of ethanol was hydrogenated at 40 p.s.i. over 50 mg of 10% Pd/C for 16 hrs. The reaction was filtered and evaporated. The residue was purified by preparative TLC eluting with 2% TEA/10% methanol/88% ethyl acetate to afford 150 mg of title product.

Analysis: C₃₀ H₃₈ N₄ O₆.3H2O Calc: C, 59.59; H, 7.33; N, 9.29 Found: C, 59.66; H, 7.65; N, 9.61 

What is claimed is:
 1. A compound of Formula (I): ##STR37## or a pharmaceutically acceptable salt thereof wherein: R is C₁₋₆ alkyl;R¹ is C₁₋₆ alkyl or C₁₋₆ alkoxy-C₁₋₆ alkyl; M is(1) hydrogen, (2) C₁₋₆ alkyl, (3) hydroxy C₁₋₆ alkyl, (4) halo C₁₋₆ alkyl, (5) C₂₋₆ alkenyl, or (6) C₁₋₆ alkoxy-C₁₋₆ alkyl; Ra and Rb are each individually(1) hydrogen, (2) C₁₋₆ alkyl, (3) halo, (4) carboxy, (5) C₁₋₆ alkoxy, (6) phenyl, (7) C₁₋₆ alkylcarbonyl, (8) di-(C₁₋₆ alkyl)amino; (9) hydroxy; R² and R³ are each independently(1) hydrogen, (2) C₁₋₆ alkyl, (3) halo, (4) C₁₋₆ alkoxy, (5) phenyl, (6) C₁₋₆ alkylcarbonyl, (7) aminoC₂₋₃ alkyloxy carbonyl wherein the amino is optionally mono or di substituted with C₁₋₆ alkyl, (8) aminoC₂₋₃ alkylamino carbonyl wherein the amino is optionally mono or di substituted with C₁₋₆ alkyl, (9) hydroxy, (10) aminocarbonyl wherein the amino is optionally mono or di substituted with C₁₋₆ alkyl, (11) hydroxymethyl, (12) aminocarbonyloxy C₁₋₃ alkyl, wherein the amino is optionally mono or di substituted with C₁₋₆ alkyl, (13) cyano, (14) morpholinocarbonylphenyl, (15) amino wherein the amino is optionally mono or di substituted with C₁₋₆ alkyl, or (16) morpholinocarbonyl, with the proviso that R² and R³ may be joined together to form a methylenedioxy group or a furan ring, R₄ is (a) ##STR38## (b) or ##STR39## where R_(x) is carboxy C₁₋₆ alkyl, benzyloxycarbonylC₁₋₃ alkyl, or t-butoxycarbonylC₁₋₃ alkyl,wherein Q is a covalent bond, or ##STR40## wherein R⁵ and R⁶ are each individually C₁₋₃ alkyl or hydrogen, Y is ##STR41## R₁₂ is hydrogen or C₁₋₃ alkyl; R₇ and R₈ are each individually(a) hydrogen, (b) C₁₋₆ alkyl, (c) C₁₋₆ alkyloxy C₂₋₃ alkyl, (d) hydroxy C₂₋₆ alkyl, (e) polyhydroxyC₂₋₆ alkyl, (f) carboxamido C₁₋₆ alkyl, (g) C₁₋₆ alkanoyl, (h) substituted phenyl or phenyl C₁₋₆ alkyl, wherein the substitutents are X₁ and X₂ as defined immediately below, (i) C₂₋₆ alkenyl, (j) C₆₋₁₀ cycloalkenyl, (k) heteroaryl C₁₋₆ alkyl wherein the hetero aryl is selected from pyridinyl, imidazolyl, triazolyl, benzylimidazolyl, and furyl, (l) carboxy C₁₋₆ alkyl, (m) carbo C₁₋₆ alkoxy C₁₋₃ alkyl, (n) phenylsulfonyl, (o) C₁₋₆ alkylsulfonyl, (p) benzyloxy, (q) morpholinyl C₁₋₃ alkylsulfonyl, (r) tetrahydropyranyl, (s) aminoC₁₋₃ alkylsulfonyl wherein the amino is optionally mono or di substituted with C₁₋₆ alkyl, (t) aminocarbonyl wherein the amino is optionally mono or disubstituted with C₁₋₆ alkyl, (u) aminocarbonyloxyC₂₋₆ alkyl wherein the amino is optionally mono or di substituted with C₁₋₆ alkyl, (v) azabicyclo of 7 to 12 atoms, (w) di C₁₋₃ alkylamino C₂₋₆ alkyl wherein the amino is optionally mono or di substituted with C₁₋₆ alkyl, (x) bicycloalkyl of 7 to 12 atoms, (y) C₃₋₁₀ cycloalkyl optionally substituted with C₁₋₆ alkyl, (z) pyrazolidinyl, (aa) substituted piperidinyl or prrrolidinyl wherein the substitutent is hydrogen, C₁₋₃ alkyl, hydroxy C₁₋₃ alkylbenzyl, carboxamido or amino wherein the amino is optionally mono or di substituted with C₁₋₆ alkyl, (bb) substituted pyrrolidinyl wherein the substitutent is carboxamido or amino wherein the amino is optionally mono or di substituted with C₁₋₆ alkyl, (cc) pyrimidinyl, (dd) phosphonoC₁₋₆ alkyl, or (ee) α-C₁₋₃ alkyl benzyl or mono or di substituted benzyl or mono or di substituted pyridylmethyl, wherein the substitutents are X₁ and X₂,wherein X₁ is(1) hydrogen, (2) halo, (3) C₁₋₆ alkyl, (4) halo-C₁₋₆ alkyl, (5) C₂₋₆ alkenyl, (6) hydroxy-C₁₋₆ alkyl, (7) C₁₋₆ alkylcarbonyl, (8) C₁₋₆ alkylcarbonylamino, (9) CN, (10) CF₃, (11) CH₃ O, (12) amino wherein the amino is optionally mono or di substituted with C₁₋₆ alkyl, (13) carboxy, or (14) phenylsulfonylaminocarbonyl; X₂ is hydrogen, halo or C₁₋₆ alkyl; n is 1, 2, 3, 4 or 5; R⁹ is selected from hydrogen, C₁₋₄ alkyl, and C₁₋₃ alkoxyC₂₋₃ alkyl; or phenyl, phenyl C₁₋₃ alkyl, pyridyl, and pyridyl C₁₋₃ alkyl; R₁₀ and R₁₁ are each independently selected from hydrogen, C₁₋₄ alkyl, and C₁₋₃ alkoxy C₁₋₃ alkyl, or are together O═; orwherein R₇ and R₈ are joined together with the nitrogen to which they are attached to form mono or di substituted ring selected from(1) piperidinyl or homopiperdinyl, (2) piperazinyl, (3) morpholinyl, thiomorpholinyl or 1,1-dioxo-4-thiomorpholinyl, (4) pyrroylidinyl, (5) pyrryl, (6) imidazolyl, (7) triazolyl, (8) saturated azabicyclo of 7 to 12 atoms, (9) azaspiro having 3 to 9 carbon atoms, said ring being saturated, (10) tetrazolyl, (11) pyrazolidinyl, (12) azetidinyl, or (13) diazabicyclo ring of 7-12 atoms,wherein the substitutents are each selected from the group consisting of hydrogen and C₁₋₃ alkyl, benzyloxycarbonyl,phenyl C₁₋₃ alkyl amino carbonyl, hydroxy C₁₋₃ alkyl, C₁₋₆ alkyloxy, C₁₋₄ alkyloxy carbonyl, aminocarbonyl wherein the amino is optionally mono or di substituted with C₁₋₆ alkyl, and oxo; or --N(R7)R8 is--NH--(CH₂)₃ --C(H)(NH₂)--C(O)OH, or NH₂ --(CH₂)₃ --C(H)(NH)--C(O)OH; R₈ and R₉ are joined together to form a mono or di substituted saturated monocyclic ring of 6 to 7 atoms and having two hetero atoms which are the nitrogens to which R₈ and R₉ are attached; or R₉ and R₁₀ are joined together to form a mono or di substituted monocyclic saturated ring of 5 to 7 atoms and having one hetero atom which is the nitrogen to which R₉ is attached; or wherein R₉ and R₁₂ are joined together to form a mono or di substituted saturated monocyclic ring of 5, 6, or 7 atoms, said ring having one hetero atom which is the nitrogen to which R₉ is attached; or wherein R₁₀ and R₁₂ are joined together with the carbons to which they are attached to form a mono or di substituted saturated monocyclic ring of 5, 6, or 7 carbon atoms; or wherein R₈ and R₁₁ are joined together to form a mono or di substituted saturated monocyclic ring of 5, 6, or 7 atoms, said ring having one hetero atom which is the nitrogen to which R₈ is attached, and the substituents are independently selected from hydrogen and C₁₋₃ alkyl.
 2. A compound of formula I according to claim 1wherein Q is a covalent bond, Y is ##STR42## and R₄ is ##STR43##
 3. A compound according to claim 2 whereinR is C₁₋₆ alkyl; R¹ is C₁₋₆ alkyl or C₁₋₆ alkoxy-C₁₋₆ alkyl; M is(1) hydrogen, (2) C₁₋₆ alkyl, (3) hydroxy C₁₋₆ alkyl, (4) halo C₁₋₆ alkyl, (5) C₂₋₆ alkenyl, or (6) C₁₋₆ alkoxy-C₁₋₆ alkyl; Ra is(1) hydrogen, (2) C₁₋₆ alkyl, (3) halo, (4) carboxy, (5) C₁₋₆ alkoxy, (6) phenyl, (7) C₁₋₆ alkylcarbonyl, (8) amino wherein the amino may be optionally mono or di substituted with C₁₋₆ alkyl; Rb is hydrogen or C₁₋₃ alkyl, R² and R³ are each independently(1) hydrogen, (2) C₁₋₆ alkyl, (3) halo, (5) C₁₋₆ alkoxy, (6) phenyl, (7) C₁₋₆ alkylcarbonyl, (8) di-(C₁₋₆ alkyl)amino, or with the proviso that when Rb is hydrogen, R² and R³ may be joined together to form a methylenedioxy group or a furan ring; R₄ is ##STR44## wherein Q is a covalent bond Y is ##STR45## R₁₂ is hydrogen or C₁₋₃ alkyl; R₇ and R₈ are each individually(a) hydrogen, (b) C₁₋₆ alkyl, (c) C₁₋₆ alkyloxy C₂₋₃ alkyl, (d) hydroxy C₂₋₆ alkyl, (e) carboxamido C₁₋₆ alkyl, (f) C₁₋₆ alkanoyl, (g) phenyl or phenyl C₁₋₆ alkyl, (h) C₂₋₆ alkenyl, (i) C₆₋₁₀ cycloalkenyl, (j) heteroaryl C₁₋₆ alkyl wherein the heteroaryl selected form pyridinyl, imidazolyl, triazolyl, benzylimidazolyl, and furyl, (k) carboxy C₁₋₆ alkyl, (l) C₁₋₆ alkylsulfonyl, (m) benzyloxy, (n) morpholinyl C₁₋₃ alkylsulfonyl, (o) aminoC₁₋₃ alkylsulfonyl wherein the amino is optionally substituted with C₁₋₆ alkyl, (p) aminocarbonyl wherein the amino is optionally substituted with C₁₋₆ alkyl, (q) aminocarbonyloxyC₂₋₆ alkyl wherein the amino is optionally substituted with C₁₋₆ alkyl, (r) amino C₂₋₆ alkyl wherein the amino is optionally substituted with C₁₋₆ alkyl, (s) pyrazolidinyl, (t) piperidinyl, (u) pyrrolidinyl (v) pyrimidinyl, (w) C₃₋₇ cycloalkyl, (x) α-C₁₋₃ alkyl benzyl or mono or di substituted benzyl or mono or di substituted pyridylmethyl, wherein the substitutents are X₁ and X₂,wherein X₁ is(1) hydrogen, (2) halo, (3) C₁₋₆ alkyl, (4) halo-C₁₋₆ alkyl, (5) C₂₋₆ alkenyl, (6) hydroxy-C₁₋₆ alkyl, (7) C₁₋₆ alkylcarbonyl, (8) C₁₋₆ alkylcarbonylamino; (9) amino wherein the amino is optionally substituted with C₁₋₆ alkyl; or (10) carboxy, X₂ is hydrogen, halo or C₁₋₆ alkyl; n is 1, 2, 3 or 4; R₁₀ and R₁₁ are each independently selected from hydrogen, C₁₋₄ alkyl, and C₁₋₃ alkoxy C₁₋₃ alkyl; orwherein R₇ and R₈ are joined together with the nitrogen to which they are attached to form mono or di substituted ring of selected from (1) piperidinyl, (2) piperazinyl, (3) morpholinyl, (4) pyrroylidinyl, (5) pyrryl, (6) imidazolyl, (7) triazolyl, (8) tetrazolyl, (9) pyrazolidinyl, or (10) azetidinyl, wherein the substituents are each selected from the group consisting of hydrogen and C₁₋₃ alkyl, benzyloxycarbonyl, phenyl C₁₋₃ alkyl amino carbonyl, pyrrolidinyl, methyl, hydroxy C₁₋₃ alkyl, C₁₋₆ alkyloxy, C₁₋₄ alkyloxy carbonyl, and oxo; or wherein R₁₀ and R₁₂ are joined together to form a mono or di substituted saturated monocyclic ring of 5, 6, or 7 carbon atoms; or wherein R₈ and R₁₁ are joined together with the nitrogen to which R₈ is attached to form a mono or di substituted saturated monocyclic ring of 5, 6, or 7 atoms, said ring having one hetero atom which is the nitrogen to which R₈ is attached, and the substituents are independently selected from Hydrogen and C₁₋₃ alkyl.
 4. A compound according to claim 3wherein R is C₁₋₃ alkyl; R₁ is C₁₋₃ alkyl; M is(a) C₁₋₆ alkyl, or (b) C₂₋₆ alkenyl; R² is(a) hydrogen (b) C₁₋₆ alkyl, or C₁₋₆ alkoxy, and R³ is hydrogen, or R² and R³ are joined together to form a methylenedioxy group or a furan ring; R₇ and R₈ are each independently selected from(a) hydrogen, (b) C₁₋₃ alkyl, (c) C₁₋₃ alkoxy C₂₋₃ alkyl, (d) substituted benzyl wherein the substituents are X₁ and X₂ wherein X₁ is hydrogen and X₂ is(1) hydrogen, (2) halo, or (3) C₁₋₃ alkyl; n is 1, 2 or 3, and R₁₀ and R₁₁ are each independently selected from hydrogen, C₁₋₄ alkyl, and C₁₋₃ alkoxy C₁₋₃ alkyl; or R₇ and R₈ are joined together to form a substituted ring selected from(a) piperidinyl, (b) piperazinyl, and (c) morpholinyl; or wherein R₁₀ and R₁₂ are joined together with the carbons to which they are attached to form a mono or di substituted saturated monocyclic ring of 5, 6, or 7 carbon atoms; or wherein R₈ and R₁₁ are joined together to form a mono or di substituted saturated monocyclic ring of 5, 6, or 7 atoms, said ring having one hetero atom which is the nitrogen to which R₈ is attached, and the substituents are independently selected from Hydrogen and C₁₋₃ alkyl.
 5. A compound according to claim 4 whereinR is methyl or ethyl; R₁ is methyl or ethyl; M is(a) C₁₋₄ alkyl, or (b) C₂₋₃ alkenyl; R² is(a) hydrogen, (b) C₁₋₃ alkyl, or C₁₋₃ alkoxy, and R³ is hydrogen, or R² and R³ are joined together to form a methylenedioxy group or a furan ring; n is 1 or 2; R₁₀ is selected from(a) C₁₋₃ alkyl, (b) C₁₋₃ alkoxy C₂₋₃ alkyl, (c) hydrogen, R₇ and R₈ are independently selected from(a) hydrogen, (b) cyclopropyl, (c) C₁₋₃ alkyl, (d) C₁₋₃ alkoxy C₂₋₃ alkyl,or R₇ and R₈ are joined together with the nitrogen to which they are attached to form a substituted ring selected from(a) piperidinyl, and (b) morpholinyl; orwherein R₁₀ and R₁₂ are joined together with the carbons to which they are attached to form a mono or di substituted saturated monocyclic ring of 5, 6, or 7 carbon atoms; or wherein R₈ and R₁₁ are joined together to form a mono or di substituted saturated monocyclic ring of 5, 6, or 7 atoms, said ring having one hetero atom which is the nitrogen to which R₈ is attached, and the substituents are independently selected from Hydrogen and C₁₋₃ alkyl.
 6. A compound according to claim 1 whereinQ is a covalent bond, R₄ is ##STR46## and Y is ##STR47##
 7. A compound according to claim 6 whereinR is C₁₋₆ alkyl; R¹ is C₁₋₆ alkyl or C ₁₋₆ alkoxy-C₁₋₆ alkyl; M is(1) hydrogen, (2) C₁₋₆ alkyl, (3) hydroxy C₁₋₆ alkyl, (4) halo C₁₋₆ alkyl, (5) C₂₋₆ alkenyl, or (6) C₁₋₆ alkoxy-C₁₋₆ alkyl; Ra is(1) hydrogen, (2) C₁₋₆ alkyl, (3) halo, (5) C₁₋₆ alkoxy, (6) phenyl, (7) C₁₋₆ alkylcarbonyl, (8) di-(C₁₋₆ alkyl)amino; Rb is hydrogen or C₁₋₆ alkyl, R² and R³ are each independently(1) hydrogen, (2) C₁₋₆ alkyl, (3) halo, (5) C₁₋₆ alkoxy, (6) phenyl, (7) C₁₋₆ alkylcarbonyl, (8) di-(C₁₋₆ alkyl)amino, or R² and R³ may be joined together to form a methylenedioxy group or a furan ring; R₄ is ##STR48## wherein Q is a covalent bond, Y is ##STR49## R₁₂ is hydrogen or C₁₋₃ alkyl; R₇ and R₈ are each individually(a) hydrogen, (b) C₁₋₆ alkyl, (c) C₁₋₆ alkyloxy C₂₋₃ alkyl, (d) hydroxy C₂₋₆ alkyl, (e) carboxamido C₁₋₆ alkyl, (f) C₁₋₆ alkanoyl, (g) phenyl or phenyl C₁₋₆ alkyl, (h) C₂₋₆ alkenyl, (i) C₆₋₁₀ cycloalkenyl, (j) heteroaryl C₁₋₆ alkyl wherein the heteroaryl selected from pyridinyl, imidazolyl, triazolyl, benzylimidazolyl, and furyl, (k) carboxy C₁₋₆ alkyl or carboC₁₋₆ alkoxyC₁₋₆ alkyl, (l) C₁₋₆ alkylsulfonyl, (m) benzyloxy, (n) morpholinyl C₁₋₃ alkylsulfonyl, (o) aminoC₁₋₃ alkylsulfonyl wherein the amino may be optionally substituted with C₁₋₆ alkyl, (p) aminocarbonyl wherein the amino may be optionally substituted with C₁₋₆ alkyl, (q) aminocarbonyloxyC₁₋₆ alkyl wherein the amino may be optionally substituted with C₁₋₆ alkyl, (r) amino C₁₋₆ alkyl wherein the amino may be optionally substituted with C₁₋₆ alkyl, (s) pyrazolidinyl, (t) piperidinyl, (u) pyrrolidinyl (v) pyrimidinyl, (w) C₃₋₇ cycloalkyl, (x) α-C₁₋₃ alkyl benzyl or mono or di substituted benzyl or mono or di substituted pyridylmethyl, wherein the substitutents are X₁ and X₂,wherein X₁ is(1) hydrogen, (2) halo, (3) C₁₋₆ alkyl, (4) halo-C₁₋₆ alkyl, (5) C₂₋₆ alkenyl, (6) hydroxy-C₁₋₆ alkyl, (7) C₁₋₆ alkylcarbonyl, (8) C₁₋₆ alkylcarbonylamino; (9) di-C₁₋₃ alkylamino; or (10) carboxy, X₂ is hydrogen, halo or C₁₋₆ alkyl; n is 1, 2, 3 or 4; R₉ is selected from hydrogen, C₁₋₄ alkyl, and C₁₋₃ alkoxyC₁₋₃ alkyl; R₁₀ and R₁₁ are each independently selected from hydrogen, C₁₋₄ alkyl, and C₁₋₃ alkoxy C₁₋₃ alkyl; orwherein R₇ and R₈ are joined together with the nitrogen to which they are attached to form mono or di substituted ring selected from(1) piperidinyl, (2) piperazinyl, (3) morpholinyl, (4) pyrroylidinyl, (5) pyrryl, (6) imidazolyl, (7) triazolyl, (8) tetrayolyl, (9) pyrazolidinyl, or (10) azetidinyl, wherein the substituents are each selected from the group consisting of hydrogen and C₁₋₃ alkyl, benzyloxycarbonyl, phenyl C₁₋₃ alkyl amino carbonyl, pyrrolidinyl, methyl, hydroxy C₁₋₃ alkyl, C₁₋₆ alkyloxy, C₁₋₄ alkyloxy carbonyl, and oxo; or R₈ and R₉ are joined together to form a mono or di substituted saturated monocyclic ring of 6 to 7 atoms and having two hetero atoms which are the nitrogens to which R₈ and R₉ are attached; said rings selected from piperazinyl and homopiperazinyl; or R₉ and R₁₀ are joined together to fonn a mono or di substituted monocyclic saturated ring of 5 to 7 atoms and having one hetero atom which is the nitrogen to which R₉ is attached; or wherein R₉ and R₁₂ are joined together with the nitrogen to which R₉ is attached to form a mono or di substituted saturated monocyclic ring of 5, 6, or 7 atoms, said ring having one hetero atom which is the nitrogen to which R₉ is attached; or wherein R₁₀ and R₁₂ are joined together with the carbons to which they are attached to form a mono or di substituted saturated monocyclic ring of 5, 6, or 7 carbon atoms; or wherein R₈ and R₁₁ are joined together to form a mono or di substituted saturated monocyclic ring of 5, 6, or 7 atoms, said ring having one hetero atom which is the nitrogen to which R₈ is attached, and the substituents are independently selected from hydrogen and C₁₋₃ alkyl.
 8. A compound according to claim 7 whereinR is C₁₋₃ alkyl; R₁ is C₁₋₃ alkyl; M is(a) C ₁₋₆ alkyl, or (b) C₂₋₆ alkenyl; R² is(a) hydrogen (b) C₁₋₆ alkyl, or C₁₋₆ alkoxy, and R³ is hydrogen, or R² and R³ are joined together to form a methylenedioxy group or a furan ring; R₇ and R₈ are each independently selected from(a) hydrogen, (b) C₁₋₃ alkyl, (c) C₁₋₃ alkoxy C₂₋₃ alkyl, (d) C₃₋₇ cycloalkyl, (e) hydroxyC₂₋₃ alkyl, (f) carboC₁₋₄ alkoxymethyl, (g) substituted benzyl wherein the substituents are X₁ and X₂ wherein X₁ is hydrogen and X₂ is(1) hydrogen, (2) halo, or (3) C₁₋₃ alkyl; n is 1, 2 or 3, and R₉, R₁₀ and R₁₁ are each independently selected from hydrogen, C₁₋₄ alkyl, and C₁₋₃ alkoxy C₁₋₃ alkyl; or R₇ and R₈ are joined together with the nitrogen to which they are attached to form a substituted ring selected from(a) piperidinyl, (b) piperazinyl, and (c) morpholinyl;or R₈ and R₉ are joined together to form a mono or di substituted saturated monocyclic ring of 6 to 7 atoms and having two hetero atoms which are the nitrogens to which R₈ and R₉ are attached.
 9. A compound according to claim 8 whereinR is methyl or ethyl; R₁ is methyl or ethyl; M is(a) C₁₋₄ alkyl, or (b) C₂₋₃ alkenyl; R² is(a) hydrogen, (b) C₁₋₃ alkyl, or C₁₋₃ alkoxy, and R³ is hydrogen, or R² and R³ are joined together to form a methylenedioxy group or a furan ring; n is 1 or 2; R₉ and R₁₀ are each independently selected from(a) hydrogen, (b) C₁₋₃ alkyl, (c) C₁₋₃ alkoxy C₁₋₃ alkyl, R₇ and R₈ are each independently selected from (a) hydrogen, (b) C₁₋₃ alkyl, (c) cyclopropyl, (d) C₁₋₃ alkoxy C₁₋₃ alkyl, (e) hydroxyethyl, (f) carboethoxymethyl,or R₇ and R₈ are joined together with the nitrogen to which they are attached to form a mono or di substituted saturated monocyclic ring which is piperidinyl or morpholinyl, said ring optionally substituted with hydrogen or methyl; or R₈ and R₉ are joined together to form a mono or di substituted saturated monocyclic ring which is piperazinyl.
 10. A compound of Formula (I): ##STR50## or a pharmaceutically acceptable salt thereof wherein: R is C₁₋₆ alkyl;R₁ is C₁₋₆ alkyl or C₁₋₆ alkoxy-C₁₋₆ alkyl; M is(2) ethyl, propyl, butyl, pentyl or hexyl, (3) hydroxy C₁₋₆ alkyl, (4) halo C₁₋₆ alkyl, (5) C₂₋₆ alkenyl, or (6) C₁₋₆ alkoxy-C₁₋₆ alkyl; Ra and Rb are each individually(1) hydrogen, (2) C₁₋₆ alkyl, (3) halo, (4) carboxy, (5) C₁₋₆ alkoxy, (6) phenyl, (7) C₁₋₆ alkylcarbonyl, (8) di-(C₁₋₆ alkyl)amino, (9) hydroxy; R₂ is(1) hydrogen, (2) C₁₋₆ alkyl, (3) halo, (4) C₁₋₆ alkoxy, (5) phenyl, (6) C₁₋₆ alkylcarbonyl, (7) amino C₂₋₃ alkyloxy carbonyl wherein the amino is optionally mono- or di-substituted with C₁₋₆ alkyl, (8) aminoC₂₋₃ alkylamino carbonyl wherein the amino is optionally mono- or di-substituted with C₁₋₆ alkyl, (9) hydroxy, (10) aminocarbonyl wherein the amino is optionally mono- or di-substituted with C₁₋₆ alkyl, (11) hydroxymethyl, (12) aminocarbonyloxy C₁₋₃ alkyl, wherein the amino is optionally mono- or di-substituted with C₁₋₆ alkyl, (13) cyano, (14) morpholinocarbonylphenyl, (15) amino wherein the amino is optionally mono- or di-substituted with C₁₋₆ alkyl, or (16) morpholinocarbonyl; R₃ is(1) C₁₋₆ alkyl, (2) halo, (3) C₁₋₆ alkoxy, (4) phenyl, (5) C₁₋₆ alkylcarbonyl, (6) aminoC₂₋₃ alkyloxy carbonyl wherein the amino is optionally mono- or di-substituted with C₁₋₆ alkyl, (7) aminoC₂₋₃ alkylamino carbonyl wherein the amino is optionally mono- or di-substituted with C₁₋₆ alkyl, (8) hydroxy, (9) aminocarbonyl wherein the amino is optionally mono- or di-substituted with C₁₋₆ alkyl, (10) hydroxymethyl, (11) aminocarbonyloxy C₁₋₃ alkyl, wherein the amino is optionally mono- or di-substituted with C₁₋₆ alkyl, (12) cyano, (13) morpholinocarbonylphenyl, (14) amino wherein the amino is optionally mono- or di-substituted with C₁₋₆ alkyl, (15) morpholinocarbonyl, with the proviso that R² and R³ may be joined together to form a methylenedioxy group or a furan ring; R₄ is (a) ##STR51## or ##STR52## where R_(x) is carboxy C₁₋₆ alkyl, benzyloxycarbonylC₁₋₃ alkyl, or t-butoxycarbonyl-C₁₋₃ alkyl,wherein Q is a covalent bond or ##STR53## wherein R₅ and R₆ are each individually C₁₋₃ alkyl or hydrogen, Y is ##STR54## or a covalent bond; R₁₂ is hydrogen or C₁₋₃ alkyl; R₇ is(a) ethyl, propyl, butyl, pentyl or hexyl, (b) C₁₋₆ alkyloxy C₂₋₃ alkyl, (c) hydroxy C₂₋₆ alkyl, (d) polyhydroxyC₂₋₆ alkyl, (e) carboxamido C₁₋₆ alkyl, (f) C₁₋₆ alkanoyl, (g) substituted phenyl or phenyl C₁₋₆ alkyl, wherein the substituents are X₁ and X₂ as defined immediately below, (h) C₂₋₆ alkenyl, (i) C₆₋₁₀ cycloalkenyl, (j) heteroaryl C₁₋₆ alkyl wherein the hetero aryl is selected from pyridinyl, imidazolyl, triazolyl, benzylimidazolyl, and furyl, (k) carboxy C₁₋₆ alkyl, (l) carbo C₁₋₆ alkoxy C₁₋₃ alkyl, (m) phenylsulfonyl, (n) C₁₋₆ alkylsulfonyl, (o) benzyloxy, (p) morpholinyl C₁₋₃ alkylsulfonyl, (q) tetrahydropyranyl, (r) aminoC₁₋₃ alkylsulfonyl wherein the amino is optionally mono- or di-substituted with C₁₋₆ alkyl, (s) aminocarbonyl wherein the amino is optionally mono- or di-substituted with C₁₋₆ alkyl, (t) aminocarbonyloxyC₂₋₆ alkyl wherein the amino is optionally mono- or di-substituted with C₁₋₆ alkyl, (u) azabicyclo of 7 to 12 atoms, (v) di C₁₋₃ alkylamino C₂₋₆ alkyl wherein the amino is optionally mono- or di-substituted with C₁₋₆ alkyl, (w) bicycloalkyl of 7 to 12 atoms, (x) C₃₋₁₀ cycloalkyl optionally substituted with C₁₋₆ alkyl, (y) pyrazolidinyl, (z) substituted piperidinyl or pyrrolidinyl wherein the substituent is hydrogen, C₁₋₃ alkyl, hydroxy C₁₋₃ alkylbenzyl, carboxamido or amino wherein the amino is optionally mono- or di-substituted with C₁₋₆ alkyl, (aa) substituted pyrrolidinyl wherein the substituent is carboxamido or amino wherein the amino is optionally mono- or di-substituted with C₁₋₆ alkyl, (bb) pyrimidinyl, (cc) phosphonoC₁₋₆ alkyl, or (dd) α-C₁₋₃ alkyl benzyl or mono- or di-substituted benzyl or mono- or di-substituted pyridylmethyl, wherein the substituents are X₁ and X₂, R₈ is(a) C₁₋₆ alkyl, (b) C₁₋₆ alkyloxy C₂₋₃ alkyl, (c) hydroxy C₂₋₆ alkyl, (d) polyhydroxyC₂₋₆ alkyl, (e) carboxamido C₁₋₆ alkyl, (f) C₁₋₆ alkanoyl, (g) substituted phenyl or phenyl C₁₋₆ alkyl, wherein the substituents are X₁ and X₂ as defined immediately below, (h) C₂₋₆ alkenyl, (i) C₆₋₁₀ cycloalkenyl, (j) heteroaryl C₁₋₆ alkyl wherein the hetero aryl is selected from pyridinyl, imidazolyl, triazolyl, benzylimidazolyl, and furyl, (k) carboxy C₁₋₆ alkyl, (l) carbo C₁₋₆ alkoxy C₁₋₃ alkyl, (m) phenylsulfonyl, (n) C₁₋₆ alkylsulfonyl, (o) benzyloxy, (p) morpholinyl C₁₋₃ alkylsulfonyl, (q) tetrahydropyranyl, (r) aminoC₁₋₃ alkylsulfonyl wherein the amino is optionally mono- or di-substituted with C₁₋₆ alkyl, (s) aminocarbonyl wherein the amino is optionally mono- or di-substituted with C₁₋₆ alkyl, (t) aminocarbonyloxyC₂₋₆ alkyl wherein the amino is optionally mono- or di-substituted with C₁₋₆ alkyl, (u) azabicyclo of 7 to 12 atoms, (v) di C₁₋₃ alkylamino C₂₋₆ alkyl wherein the amino is optionally mono- or di-substituted with C₁₋₆ alkyl, (w) bicycloalkyl of 7 to 12 atoms, (x) C₃₋₁₀ cycloalkyl optionally substituted with C₁₋₆ alkyl, (y) pyrazolidinyl, (z) substituted piperidinyl or pyrrolidinyl wherein the substituent is hydrogen, C₁₋₃ alkyl, hydroxy C₁₋₃ alkylbenzyl, carboxamido or amino wherein the amino is optionally mono- or di-substituted with C₁₋₆ alkyl, (aa) substituted pyrrolidinyl wherein the substituent is carboxamido or amino wherein the amino is optionally mono- or di-substituted with C₁₋₆ alkyl, (bb) pyrimidinyl, (cc) phosphonoC₁₋₆ alkyl, or (dd) α-C₁₋₃ alkyl benzyl or mono- or di-substituted benzyl or mono- or di-substituted pyridylmethyl, wherein the substituents are X₁ and X₂,wherein X₁ is(1) hydrogen, (2) halo, (3) C₁₋₆ alkyl, (4) halo-C₁₋₆ alkyl, (5) C₂₋₆ alkenyl, (6) hydroxy-C₁₋₆ alkyl, (7) C₁₋₆ alkylcarbonyl, (8) C₁₋₆ alkylcarbonylamino, (9) CN, (10) CF₃, (11) CH₃ O, (12) amino wherein the amino is optionally mono or di substituted with C₁₋₆ alkyl, (13) carboxy, or (14) phenylsulfonylaminocarbonyl; X₂ is hydrogen, halo or C₁₋₆ alkyl; n is 1, 2, 3, 4 or 5; R₉ is selected from hydrogen, C₁₋₄ alkyl, and C₁₋₃ alkoxyC₂₋₃ alkyl; or phenyl, phenyl C₁₋₃ alkyl, pyridyl, and pyridyl C₁₋₃ alkyl; R₁₀ and R₁₁ are each independently selected from hydrogen, C₁₋₄ alkyl, and C₁₋₃ alkoxy C₁₋₃ alkyl, or are together O═; orwherein R₇ and R₈ are joined together with the nitrogen to which they are attached to form mono- or di-substituted ring selected from(1) piperidinyl or homopiperdinyl, (2) piperazinyl, (3) morpholinyl, thiomorpholinyl or 1,1-dioxo-4-thio-morpholinyl, (4) pyrroylidinyl, (5) pyrryl, (6) imidazolyl, (7) triazolyl, (8) saturated azabicyclo of 7 to 12 atoms, (9) azaspiro having 3 to 9 carbon atoms, said ring being saturated, (10) tetrazolyl, (11) pyrazolidinyl, (12) azetidinyl, or (13) diazabicyclo ring of 7-12 atoms,wherein the substituents are each selected from the group consisting of hydrogen and C₁₋₃ alkyl, benzyloxycarbonyl, phenyl C₁₋₃ alkyl amino carbonyl, pyrrolidinylmethyl, hydroxy C₁₋₃ alkyl, C₁₋₆ alkyloxy, C₁₋₄ alkyloxy carbonyl, aminocarbonyl wherein the amino is optionally mono- or di-substituted with C₁₋₆ alkyl, and oxo; or --N(R7)R8 is--NH--(CH₂)₃ --C(H)(NH₂)--C(O)OH, or NH₂ --(CH₂)₃ --C(H)(NH)--C(O)OH; R₈ R₉ are joined together to form a mono- or di-substituted saturated monocyclic ring of 6 to 7 atoms and having two hetero atoms which are the nitrogens to which R₈ are attached; or R₉ and R₁₀ are joined together to form a mono- or di-substituted monocyclic saturated ring of 5 to 7 atoms and having one hetero atom which is the nitrogen to which R₉ is attached; or wherein R₉ and R₁₂ are joined together to form a mono- or di-substituted saturated monocyclic ring of 5, 6, or 7 atoms, said ring having one hetero atom which is the nitrogen to which R₉ is attached; or wherein R₁₀ and R₁₂ are joined together with the carbons to which they are attached to form a mono- or di-substituted saturated monocyclic ring of 5, 6, or 7 carbon atoms; or wherein R₈ and R₁₁ are joined together to form a mono- or disubstituted saturated monocyclic ring of 5, 6, or 7 atoms, said ring having one hetero atom which is the nitrogen to which R₈ is attached, and the substituents are independently selected from hydrogen and C₁₋₃ alkyl.
 11. A compound according to the Formula ##STR55## wherein A is:-- CH₂ CH₂ N(CH₃)₂, 2 --CH₂ CO₂ H, 3 --CH₂ --C(O)N(CH₂ CH₂ OH)₂, 4 --CH₂ --C(O)N(CH₃)CH₂ C(O)NH₂, 5 --CH₂ C(O)NH--C(CH₂ OH)₃, 6 --CH₂ C(O)N(CH₃)₂, 7 --CH₂ CH₂ N(CH₃)Ac, 10 --CH(CH₃)CO₂ CH₂ Ph, 11 --CH(CH₃)CO₂ H, 12 --CH(CH₃)C(O)N(Et)₂, 13 --CH(CH₃)CH₂ N(CH₃)₂, 14 --CH₂ CH₂ CH₂ N(CH₃)₂, 16 --CH₂ CH₂ N(Et)₂, 17 --CH₂ CH₂ (4--morpholinyl ), 18 --CH₂ CH₂ CH₂ CH₂ N(CH₃)₂, 19 --CH₂ C(O)--Pro--NHCH₂ Ph, 20 --CH₂ C(CH₃)₂ N(CH₃)₂, 21 --CH₂ CH₂ N(i--Pr)₂, 23 --CH₂ CH₂ N(n--Bu)₂, 24 --CH₂ CH₂ CH₂ CH₂ CH₂ CH₂ N(CH₃)₂, 25 --CH₂ CH₂ (1-piperazinyl), 26 --CH₂ CH₂ (4-methyl-1-piperazinyl), 28 --CH₂ CH₂ N(Ph)₂, 29 --CH₂ CH₂ N(CH₂ CH═CH₂)₂, 30 --CH₂ CH(Ph)N(CH₃)₂, or 31 --CH₂ CH₂ N(CH₃)CH₂ Ph.
 12. A compound according to claim 1 of the Formula ##STR56## wherein A is-- CH₂ CH₂ N(CH₃)₂, 2 --CH₂ CH₂ CH₂ N(CH₃)₂, 3 --CH₂ CH₂ N(Et)₂, 4 --CH₂ CH₂ -(4-morpholinyl), 5 --CH(CH₃)CH₂ N(CH₃)₂, 6 --CH₂ -C(CH₃)₂ N(CH₃)₂, or 8 --CH₂ CH₂ N(CH₃)CH₂ Ph.
 13. A compound of the Formula ##STR57## wherein A is-- N(H₂ CH₂ OH)₂, 2 4-methyl-1-piperazinyl, 3 4-morpholinyl, 4 --NHCH₂ CH₂ N(CH₃)₂, 5 --N(CH₃)CH₂ CH₂ N(CH₃)₂, 6 --NCHC₂ CH₂ CH₂ N(CH₃)₂, 7 --NHCH₂ CH₂ --(4-pyridyl), 8 --NHCH₂ CO₂ H, 9 --NHCH(CH₃)CO₂ H, 10 --NHCH₂ C(O)N(CH₂ CH₂ OH)₂, 11 --N(CH₃)CH₂ CO₂ H, 12 --NHCH(CH₃)C(O)N(CH₂ CH₂ OH)₂, 13 --N(CH₃)CH₂ C(O)N(CH₂ CH₂ OH)₂, 14 --N(CH₃)CH₂ CH₂ --(4-morpholinyl), 15 --N(CH₃)CH₂ CH₂ N(CH₂ CH₂ OCH₃)₂, 16 --N(CH₃)CH₂ CH₂ CH₂ N(Et)₂, 17 --N(CH₃)CH₂ CH₂ CH₂ N(CH₃)₂, 18 --NHCH₂ CH(CH₃)N(CH₃)₂, 19 --N(CH₃)CH₂ CH₂ N(i-pr)₂, 2-- N(n-pro)₂, 21 --N(Et)₂, 22 3-chloroanilino-, 23 3-methoxyanilino-, 24 4-fluoroanilino-, 25 --N(CH₃)CH₂ CH₂ CH₂ CO₂ H, 26 --N(CH₃)CH₂ CH₂ CH₂ C(O)NHSO₂ Ph, 27 --N(CH₃)CH₂ CH₂ CH₂ N(CH₃)CH₂ Ph, 28 --N(CH₃)₂, 29 --N(CH₃)CH₂ Ph, 30 --N(CH₃)CH₂ CH₂ N(CH₃)CH₂ Ph, 31 --NH--O--CH₂ Ph, 32 --N(CH₃)(4-carboxyphenyl), or 33 --N(CH₃)(4-benzenesulfonylaminocarbonylphenyl).
 14. A compound selected from the group consisting of:(a) [S-(R*,S*)]-2-[4-[[[2-(dimethylamino)ethyl]methyl-amino]carbonyl]-phenoxy]3,3-diethyl-N-[1-(4-methylphenyl)butyl]-4-oxo-1-azetidinecarboxamide, (b) [S-(R*,S*)]-2-[4-[[[2-(dimethylamino)ethyl]methyl-amino]carbonyl]phenoxy]3,3-diethyl-N-[1-(3,4-methylenedioxy-phenyl)butyl]-4-oxo-1--azetidine-carboxamide, (c) [S-(R*,S*)]-2-[4-[[4-methylpiperazin-1-yl]carbonyl]phenoxy]-3,3-diethyl-N-[1-(4-methylphenyl)butyl]-4-oxo-1-azetidinecarboxamide, (d) [S-(R*,S*)]-2-[4-[[4-methylpiperazin-1-yl]carbonyl]phenoxy]-3,3-diethyl-N-[1-(3,4-methylenedioxy-phenyl)butyl]-4-oxo-1-azetidinecarboxamide, (e) [S-(R*,S*)]-2-[4-[[4-cyclopropylpiperazin-1-yl]-carbonyl]phenoxy]-3,3-diethyl-N-[1-(4-methylphenyl)butyl]-4-oxo-1-azetidinecarboxamide, (f) [S-(R*,S*)]-2-[4-[[4-cyclopropylpiperazin-1-yl]carbonyl]phenoxy]-3,3-diethyl-N-[1-(3,4-methylenedioxyphenyl)butyl]-4-oxo-1-azetidinecarboxamide, (g) [S-(R*,S*)]-2-[4-[[piperazin-1-yl]carbonyl]phenoxy]-3,3-diethyl-N-[1-(4-methylphenyl)butyl]-4-oxo-1-azetidinecarboxamide, or (h) [S-(R*,S*)]-2-[4-[[piperazin-1-yl]carbonyl]-phenoxy]-3,3-diethyl-N-[1-(3,4-methylenedioxyphenyl)butyl]-4-oxo-1-azetidinecarboxamide, (i) [S-(R*,S*)]-2-[4-[[((2-dimethylamino)ethyl)ethylamino]carbonyl]-phenoxy]-3,3-diethyl-N-[1-(4-methylphenyl)butyl]-4-oxo-1-azetidinecarboxamide, (j) [S-(R*,S*)]-2-[4-[[((2-diethylamino)ethyl)ethylamino]carbonyl]phenoxy]-3,3-diethyl-N-[1-(4-methylphenyl)butyl]-4-oxo-1-azetidinecarboxamide, (k) [S-(R*,S*)]-2-[4-[[(4-(2-hydroxyethyl))piperazin-1-yl]carbonyl]phenoxy]-3,3-diethyl-N-[1-(4-methylphenyl)butyl]-4-oxo-1-azetidinecarboxamide, (l) [S-(R*,S*)]-2-[4-[[(4-(2-hydroxyethyl))piperazin-1-yl]carbonyl]phenoxy]-3,3-diethyl-N-[1-(3,4-methylenedioxyphenyl)butyl]-4-oxo-1-azetidinecarboxamide, or (m) [S-(R*,S*)]-2-[4-[[(4-(ethoxycarbonylmethyl))piperazin-1-yl]carbonyl]phenoxy]-3,3-diethyl-N-[1-(3,4-methylenedioxyphenyl)butyl]-4-oxo-1-azetidinecarboxamide.
 15. A compound of the Formula ##STR58## wherein R is:-- CH₃, 2 4-fluorophenyl, 3 3-chlorophenyl, 4 phenyl, 5 benzyl, 6 H, 7 i-Pr, 8 i-Bu, 9 --CH₂ CO₂ Et 10 --CH₂ CO₂ H, 11 Et, 12 Pr, 13 2-pyrimidinyl, 14 --CH₂ CH₂ OC(O)NHCH₃, 15 cyclopropyl, or 16 --CH₂ CH₂ OH.
 16. A compound of the Formula ##STR59## where n and A are:

    ______________________________________                                         n            A                                                                 ______________________________________                                         2     1          4-morpholinyl,                                                3     1          --N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2,             4     0          --N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2,             5     0          --N(Et).sub.2,                                                6     0          --N(CH.sub.3)(n-Bu),                                          7     0          4-methyl-1-piperazinyl,                                       8     0          --N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)CH.sub.2 Ph,        9     0          4-cyclopropyl-1-piperazinyl, or                               10    0          1-piperazinyl,                                                11    0          4-(2-hydroxyethyl)-1-piperazinyl, or                          12    0          4-morpholinyl.                                                ______________________________________                                    


17. A compound of the formula ##STR60## wherein n, R₂, and A are:

    ______________________________________                                         n          R.sub.2  A                                                          ______________________________________                                         1     1        H        4-morpholinyl,                                         2     1        H        --N(Et).sub.2,                                         3     1        H        --N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2,                              1                                                      5     1        CH.sub.3 N(Et).sub.2,                                           6     1        CH.sub.3 N(n-Pr).sub.2,                                         7     0        Et       --N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2,                              or                                                     8     0        Et       --N(CH.sub.3)(n-Bu).                                   ______________________________________                                    


18. A compound of the Formula ##STR61## wherein n, R₃ and A are:

    ______________________________________                                         n            R.sub.3 A                                                         ______________________________________                                         2     1          H       --N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2,                              1                                                     4     0          H       --N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2,                              8                                                     5     0          H       --OCH.sub.2 CH.sub.2 N(CH.sub.3).sub.2,               6     0          H       --N(Et).sub.2, or                                     7     0          H       4-morpholinyl.                                        ______________________________________                                    


19. A compound of the Formula ##STR62## where n, R₃, R₄, and A are:

    __________________________________________________________________________     n   R.sub.3   R.sub.4         A                                                __________________________________________________________________________     1 1 H         CO.sub.2 H      4-morpholinyl,                                   2 1 H         --CO.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                 4-morpholinyl,                                   3 1 H         --CON(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                             4-morpholinyl,                                   4 1 H         --OH            --N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).s                                   ub.2,                                            5 1 H         OCH.sub.3       --N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).s                                   ub.2,                                            6 0 H         --CON(CH.sub.3).sub.2                                                                          --N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).s                                   ub.2,                                            7 0 H         --CO.sub.2 H    --N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).s                                   ub.2,                                            8 0 H         --CH.sub.2 OH   --N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).s                                   ub.2,                                            9 1 H         OCH.sub.3       --N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).s                                   ub.2,                                            10                                                                               0 H         OCH.sub.3       --N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).s                                   ub.2,                                            11                                                                               0 OCH.sub.3 H               --N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).s                                   ub.2,                                            12                                                                               1 --CH.sub.2 OCON(Et).sub.2                                                                CH.sub.3        4-morpholinyl,                                   13                                                                               1 --CON(n-Pr).sub.2                                                                        CH.sub.3        --N(Et).sub.2,                                   14                                                                               1 CON(n-Pr).sub.2                                                                          CH.sub.3        4-morpholinyl,                                   15                                                                               0 H         CN              --N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).s                                   ub.2,                                            16                                                                               0 H         OEt             --N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)CH                                   .sub.2 Ph,                                       17                                                                               0 H         2-(4-morpholinocarbonylphenyl)                                                                 --N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)CH                                   .sub.2 Ph,                                       18                                                                               0 H         OCH.sub.3       4-methyl-1-piperazinyl,                          19                                                                               0 H         Cl              --N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).s                                   ub.2,                                            20                                                                               0 H         Cl              --N(CH.sub.3)CH.sub.2 CH.sub.2 N(Et).sub.2,      21                                                                               0 H         Cl              --N(CH.sub.3)CH.sub.2 CH.sub.2 N(i-Pr).sub.2                                   ,                                                22                                                                               0 H         Cl              --N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3)CH                                   .sub.2 Ph, or                                    23                                                                               0 OCH.sub.3 CH.sub.3        --N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).s                                   ub.2.                                            __________________________________________________________________________


20. A compound according to claim 1 of the Formula ##STR63## where n, R₂, R₆, and A are:

    ______________________________________                                         No.     R.sub.2 R.sub.6  A                                                     ______________________________________                                         1       CH.sub.3                                                                               CH.sub.3 --OCH.sub.2 CH.sub.2 N(CH.sub.3).sub.2,               2       CH.sub.3                                                                               CH.sub.3 --OCH.sub.2 CH.sub.2 N(Et).sub.2,                     3       CH.sub.3                                                                               CH.sub.3 --OCH.sub.2 CH.sub.2 N(i-Pr).sub.2,                   4       CH.sub.3                                                                               CH.sub.3 --N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2,                              2                                                     5       CH.sub.3                                                                               CH.sub.3 --N(CH.sub.3 CH.sub.2 CH.sub.2 N(Et).sub.2,           6       CH.sub.3                                                                               CH.sub.3 --N(Et)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2, or        7       H       OH       --N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2.     ______________________________________                                    


21. A compound selected from the group consisting of:(a) t-Butoxycarbonylmethyl [S-(R*,S*)]4-((3,3-diethyl-1-(((1-(4-methylphenyl)butyl)amino)carbonyl)-4-oxo-2-azetidinyl)oxy)benzoate, (b) 2-(bis(2-hydroxyethyl)amino)-2-oxoethyl(S-(R*,S*))-4-((3,3-diethyl-1-(((1-(4-methyl-phenyl)butyl)amino)carbonyl)-4-oxo-2-azetidinyl) oxy)benzoate, (c) 1-methyl-2-oxo-2-(phenylmethyloxy)ethyl (2S-(1(S*),2R*,(R)))-4-((3,3-diethyl-1-(((1-(4-methylphenyl)butyl)amino)carbonyl)-4-oxo-2-azetidinyl)oxy)benzoate, (d) 1-carboxyethyl [S-(R*,S*)]4-((3,3-diethyl-1-(((1-(4-methyl-phenyl)butyl)amino)carbonyl)-4-oxo-2- azetidinyl)oxy)benzoate, (e) 2-(diethylamino)-1-methyl-2-oxoethyl [S-(R*,S,)]-4-((3,3-diethyl-1-(((1-(4-methyl-phenyl)butyl)-amino)carbonyl)-4-oxo-2- azetidinyl)oxy)benzoate (f) (S(R*,S*))-1-(((4-((3,3-diethyl-1-(((1-(4-methylphenyl)butyl)amino)carbonyl)-4-oxo-2-azetidinyl)oxy) benzoyl)oxy)acetyl)-L-proline, (g) [S-(R*,S,)]1-(((4-((3,3-diethyl-1-(((1-(4-methylphenylbutyl)amino)carbonyl)-4-oxo-2-azetidinyl)oxy)benzoyl)oxy)acetyl)-N-benzyl-L-prolinamide, (h) 2-(dimethylamino)ethyl(S-(R*,S,))-4-((3,3-diethyl-1-(((1-(4-methyl-phenyl)butyl)amino)carbonyl)-4oxo-2-azetidinyl)oxy)benzoate, (i) 1-Dimethylamino-2-propyl [S-(R*,S*)]-4-[[3,3-diethyl-1-[[[1-(4-methyl-phenyl)butyl]amino]carbonyl]-4-oxo-2-azetidinyl]oxy]benzoate, (j) 3-Dimethylamino-1-propyl [S-(R*,S*)]-4-[[3,3-diethyl-1-[[[1-(4-methyl-phenyl)butyl]amino]carbonyl]-4-oxo-2-azetidinyl]oxy]benzoate, (k) 2-Diethylaminoethyl [S-(R*,S*)]-4-[[3,3-diethyl-1-[[[1-(4-methyl-phenyl)butyl]amino]carbonyl]-4-oxo-2-azetidinyl]oxy]benzoate, (l) 2-(1-[4-morpholino]ethyl) [S-(R*,S*)]-4-[[3,3-diethyl-1-[[[1-(4-methyl-phenyl)butyl]amino]carbonyl]-4-oxo-2-azetidinyl]oxy]benzoate, (m) 4-dimethylaminobutyl [S-(R*,S*)]-4-[[3,3-diethyl-1-[[[1-(4-methyl-phenyl)butyl]amino]carbonyl]-4-oxo-2-azetidinyl]oxy]benzoate, (n) 2-dimethylamino-2-methyl-1-propyl [S-(R*,S*)]-4-[[3,3-diethyl-1-[[[1-(4-methyl-phenyl)butyl]amino]carbonyl]-4-oxo-2-azetidinyl]oxy]benzoate, (o) 2-(diisopropylamino)ethyl [S-(R*,S*)]-4-[[3,3-diethyl-1-[[[1-(4-methyl-phenyl)butyl]amino]carbonyl]-4-oxo-2-azetidinyl]oxy]benzoate, (p) Benzyl [S-(R*,S,)]-4-[2-[[4-[[3,3-diethyl-1-[[[1-(4-methylphenyl)butyl]amino]-carbonyl]-4-oxo-2-azetidinyl]oxy]benzoyl]oxy]-ethyl]-1-piperazinecarboxylate, (q) 2-(dibutylamino)ethyl [S-(R*,S*)]-4-[[3,3-diethyl-1-[[[1-(4-methyl-phenyl)butyl]amino]carbonyl]-4-oxo-2-azetidinyl]oxy]benzoate, (r) [S-(R*,S*)]-6-(dimethylamino)hexyl4-[[3,3-diethyl-1-[[[1-(4-methyl-phenyl)butyl]amino]carbonyl]-4-oxo-2-azetidinyl] oxy]-benzoate, (s) 2-(4-methyl-1-piperazinyl)ethyl [S-(R*,S*)]-4-[[3,3-diethyl-1-[[[1-(4-methyl-phenyl)butyl]amino]carbonyl]-4-oxo-2-azetidinyl]oxy]benzoate, (t) 2-(diphenylamino)ethyl[S-(R*,S*)]-4-[[3,3-diethyl-1-[[[1-(4-methyl-phenyl)butyl]amino]carbonyl]-4-oxo-2-azetidinyl]oxy]benzoate, (u) 2-(di-2-propenylamino)ethyl [S-(R*,S*)]-4-[[3,3-diethyl-1-[[[1-(4-methyl-phenyl)butyl]amino]carbonyl]-4-oxo-2-azetidinyl]oxy]benzoate, (v) 2-(dimethylamino)-2-phenylethyl[S-(R*,S*)]-4-[[3,3-diethyl-1-[[[1-(4-methyl-phenyl)butyl]amino]carbonyl]-4-oxo-2-azetidinyl] oxy]benzoate, (w) 2-[methyl(phenylmethyl)amino]ethyl [S-(R*,S*)]-4-[[3,3-diethyl-1-[[[1-(4-methyl-phenyl)butyl]amino]carbonyl]-4-oxo-2-azetidinyl]oxy]benzoate, (x) 2-(dimethylamino)ethyl[S,(R*,S*)]-4-[[3,3-diethyl-1-[[[1-(4-methyl-phenyl)butyl]amino]carbonyl]-4-oxo-2-azetidinyl] oxy]-2,6-dimethyl-benzoate, (y) 2-(diethylamino)ethyl[S-(R*,S*)]-4-[[3,3-diethyl-1-[[[1-(4-methyl-phenyl)butyl]amino]carbonyl]-4-oxo-2-azetidinyl]oxy]-2,6-dimethylbenzoate, (z) 2-[bis(1-methylethyl)amino]-ethyl [S-(R*,S*)]-4-[[3,3-diethyl-1-[[[1-(4-methyl-phenyl)butyl]amino]carbonyl]-4-oxo-2-azetidinyl]oxy]-2,6-dimethyl-benzoate.
 22. A compound which is[S-(R*,S*)]-2-[4-[[4-methylpiperazin-1-yl]carbonyl]phenoxy]-3,3-diethyl-N-[1-(3,4-methylenedioxyphenyl)butyl]-4-oxo-1-azetidinecarboxamide, or a pharmaceutically acceptable salt thereof.
 23. A pharmaceutical composition for the inhibition of human leukocyte elastase which comprises a nontoxic therapeutically effective amount of a compound which is[S-(R*,S*)]-2-[4-[[4-methylpiperazin-1-yl]carbonyl]phenoxy]-3,3-diethyl-N-[1-(3,4-methylenedioxyphenyl)butyl]-4-oxo-1-azetidinecarboxamide or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 24. A compound according to claim 1 which is(a) [S-(R*,S*)]-2-[4-[[((2-Dimethylamino)ethyl)methylamino]carbonyl]phenoxy]-3,3-diethyl-N-[1-(4-methylphenyl)butyl]-4-oxo-1-azetidinecarboxamide, (b) [S-(R*,S*)]-2-[4-[[(4-Methyl)piperazin-1-yl]carbonyl]phenoxy]-3,3-diethyl-N-[1-(4-methylphenyl)butyl]-4-oxo-1-azetidine-carboxamide, (c) [S-(R*,S*)]-2-[4-[[(4-Methyl)piperazin-1-yl]carbonyl]phenoxy]-3,3-diethyl-N-[1-3,4-methylenedioxyphenyl)butyl]-4-oxo-1-azetidinecarboxamide, (d) [S-(R*,S*)]-2-[4-[[(4-Cyclopropyl)piperazin-1-yl]carbonyl]phenoxy]-3,3-diethyl-N-[1-(4-methylphenyl)butyl]-4-oxo-1-azetidinecarboxamide, (e) [S-(R*,S*)]-2-[4-[[(4-Cyclopropyl)piperazin-1-yl]carbonyl]phenoxy]3,3-diethyl-N-[1-(3,4-methylenedioxyphenyl)butyl]-4-oxo-1-azetidinecarboxamide, (f) [S-(R*,S*)]-2-[4-[(piperazin-1-yl)carbonyl]phenoxy]-3,3-diethyl-N-[1-(4-methylphenyl)butyl]-4-oxo-1-azetidine-carboxamide, or (g) [S-(R*,S*)]-2-[4-[(piperazin-1-yl)carbonyl]phenoxy]-3,3-diethyl-N-[1-(3,4-methylenedioxyphenyl)butyl ]-4-oxo-1-azetidinecarboxamide.
 25. A pharamaceutical composition for the inhibition of human leukocyte elastase which comprises a nontoxic therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
 26. A method of treatment for the inhibition of human leukocyte elastase which comprises the administration to a subject in need of such inhibition a nontoxic therapeutically effective amount of a compound of claim
 1. 27. A compound of the Formula ##STR64## wherein A is:-- NHCH₂ CH₂ N(CH₃)₂, 2 --NH--CH₂ CO₂ H, 3 --N(CH₃)CH₂ CH₂ N(CH₃)₂, 4 --N(Et)CH₂ CH₂ N(CH₃)₂, 5 --NHCH₂ CH₂ N(Et)₂, 6 --NHCH₂ CH₂ -(4-morpholinyl), 7 --N(CH₃)CH₂ CH₂ -(4-morpholinyl), 8 --N(CH₃)CH₂ CH₂ N(CH₂ CH₂ OCH₃)₂, 9 --N(CH₃)CH₂ CH₂ N(Et)₂, 10 --N(Ph)CH₂ CH₂ N(CH₃)₂, 11 --N(CH₃)CH₂ CH₂ CH₂ N(CH₃)₂, 12 --NH CH₂ CH₂ N(i-Pr)₂, 13 --N(CH₃)CH₂ CH₂ N(O)(CH₃)₂, 14 --N(CH₃)CH₂ CH₂ N(i-Pr)₂, 15 --NH--SO₂ CH₂ CH₂ -(4-morpholinyl), 16 --NH--SO₂ CH₂ CH₂ N(CH₃)₂, 17 --NHCH₂ CH₂ -(4-imidazolyl), 18 --NHCH₂ CH₂ -(1-piperidinyl), 19 --N(CH₃)CH₂ CH₂ -(1-piperidinyl), 20 --N(CH₃)CH₂ CH₂ NHCH₃, 21 --N(CH₃)CH₂ CH₂ N(CH₃)Ac, 22 --NHCH₂ CH₂ -(1-pyrrolidinyl), 23 --N(CH₃)CH₂ CH₂ -(1-pyrrolidinyl), 2-- NHCH₂ CH₂ -(1H-1,2,4-triazol-1-yl), 25 --NH--CH₂ CH₂ -(1-imidazolyl), 26 --NH--CH₂ CH₂ -(2H-tetrazol-2-yl), 27 --NH--CH₂ CH₂ -(1H-tetrazol-1-yl), 28 --N(CH₃)CH₂ CH₂ -(4-imidazolyl), 29 --N(CH₃)CH₂ CH₂ N(CH₃)Ac, 30 --N(CH₃)CH₂ CH₂ N(CH₃)C(O)NHCH₃, 31 --N(CH₃)CH₂ CH₂ N(CH₃)SO₂ CH₃, 32 --NHCH₂ CH₂ -(1,1-dioxo-4-thiamorpholinyl), 33 4-dimethylaminobenzylamino, 34 3-dimethylaminoanilino, 35 --N(CH₃)CH₂ CH₂ -(1,1-dioxo-4-thia-morpholinyl), 36 4-dimethylaminoanilino, 37 --NHCH₂ CH₂ -(1-benzyl-1H-imidazol-2-yl), 38 --N(CH₃)CH₂ CH₂ (2-pyridyl), 39 --NHCH₂ CH₂ (4-benzyloxycarbonyl-1-piperazinyl), 40 1,2-diethylpyrazolidin-4-yl amino, 41 2-(1-S-pyrrolidinylmethyl)-1-pyrrolidinyl, 42 --NHCH₂ CH₂ (4-hydroxy-1-piperidinyl), 43 --NHCH₂ CH₂ (1-homopiperidinyl), 44 --N(CH₃)CH₂ CH₂ (1-homopiperidinyl), 45 --NHCH₂ CH₂ (3-hydroxy-1-piperidinyl), 46 --N(CH₃)CH₂ CH₂ (3-hydroxy-1-piperidinyl), 47 --N(CH₃)CH₂ CH₂ N(CH₃)CH₂ Ph, 48 --N(CH₃)CH₂ CH₂ (4-benzyloxy-1-piperidinyl), 49 --N(n-Pr)₂, 50 --N(Et)₂, 51 --N(CH₃)CH₂ CH₂ (4-hydroxy-1-piperidinyl), 52 --N(CH₃)CH₂ CH₂ (4-oxo-1-piperidinyl), 53 --NHCH₂ CH₂ (3-hydroxy-1-pyrrolidinyl), 54 --N(Et)CH₂ CH₂ (1-piperidinyl), 55 --N(CH₂ Ph)CH₂ CH₂ (1-piperidinyl), 56 4-fluoroanilino-, 57 3-chloroanilino-, 583-methoxyanilino, 59 --N(CH₂ Ph)CH₂ CH₂ N(CH₃)₂, 60 --N(CH₃)CH₂ CH₂ (3-hydroxy-1-pyrrolidinyl), 61 --N(3-picolyl)CH₂ CH₂ (1-piperidinyl), 62 --NHCH(CH₃)CH₂ CH₂ CH₂ N(Et)₂, 63 --NHCH₂ CH₂ (2-S-hydroxymethyl-1-pyrrolidinyl, 64 --N(CH₃)CH₂ CH₂ (4t-butoxycarbonyl-1-piperazinyl), 65 --N[CH₂ CH₂ N(CH₃)_(2]2), 66 --N [CH₂ CH₂ N(Et)_(2]2), 67 --N(CH₃)CH₂ CH₂ N(CH₃)(3-picolyl), 68 3,5-dimethyl-1-piperazinyl, 69 --N(CH₃)CH₂ CH₂ N(O)(CH₃)CH₂ Ph, 70 --N(CH₃)CH₂ CH₂ N(CH₃)(4-picolyl), 71 2-S-(N-benzyl-N-methylaminomethyl)-1-pyrrolidinyl, 72 --N(CH₃)CH₂ CH₂ N(CH₃)(2-picolyl), 73 --N(CH₃)CH₂ CH₂ (1-piperazinyl), 74 1-homopiperazinyl, 75 --N(CH₃)CH₂ CH₂ N(CH₃)CH₂ CH₂ Ph, 76 2-(1-R-pyrrolidinylmethyl)-1-pyrrolidinyl, 77 4-benzyl-1-homopiperazinyl, 78 --N(CH₃)CH₂ --[CH(OH)]₄ CH₂ OH, 79 --N(CH₃)CH₂ --[CH(OAc)]₄ CH₂ OAc, 80 --N(CH₃)CH₂ CH₂ N(CH₃)(1-naphthalenylmethyl), 81 --N(CH₃)CH₂ CH₂ N(CH₃)(2-naphthalenylmethyl), 82 --N(CH₃)CH₂ CH₂ N(CH₃)CH(CH₃)Ph, 83 --N(CH₃)CH₂ CH₂ N(CH₂ Ph )₂, 84 1-ethyl-3-piperidinylamino, 85 --N(CH₃)CH₂ CH₂ N(CH₃)(2-furfuryl), 86 --N(CH₃)CH₂ CH₂ CH₂ CO₂ H, 87 --N(CH₃)CH₂ CH₂ CH₂ C(O)NHSO₂ Ph, 88 --N(CH₃)CH₂ CH₂ N(CH₃)CH₂ CH═CH₂, 89 --N(CH₃)CH₂ CH₂ CH₂ N(CH₃)CH₂ Ph, 90 --N(CH₃)--(CH₂)₆ --N(CH₃)CH₂ Ph, 91 --N(CH₃)CH₂ CH₂ OH, 9-- N(CH₃)CH₂ CH₂ OC(O)N(CH₃)₂, 93 --N(CH₃)CH₂ CH₂ N(CH₃)CH₂ CO₂ -t-Bu, 94 --N(CH₃)(1-ethyl-3-piperidinyl), 95 --N(CH₃)CH₂ CH₂ N(CH₃)(tetrahydro-2H-pyran-2-yl-methyl), 96 2,2,6,6-tetramethylpiperidin-4-ylamino, 97 --N(CH₃)(4-carboxyphenyl), 98 --N(CH₃)(4-benzenesulfonylaminocarbonyl,-phenyl 99 --N(CH₃)CH₂ CH₂ N(CH₃)(4-cyanobenzyl), 100 --N(CH₃)CH₂ CH₂ N(CH₃)(4-methylbenzyl), 101 --N(CH₃)CH₂ CH₂ N(CH₃)(3-cyanobenzyl), 102 --N(CH₃)CH₂ CH₂ N(CH₃)(4-trifluoro-methylbenzyl, 103 --N(CH₃)CH₂ CH₂ N(CH₃)(3-trifluoromethyl-benzyl), 104 --N(CH₃)CH₂ CH₂ (CH₃)(4-fluorobenzyl), 105 --NHCH(CH₃)PH(O)OH, 106 --N(CH₃)CH₂ CH₂ N(H₃)(cyclopropylmethyl), 107 --N(CH₃)CH₂ CH(Ph)N(CH₃)₂, 108 --N(CH₃)₂, 109 --N(CH₃)CH₂ Ph, 110 --N(CH₃)(1-benzyl-3-piperidinyl), 111 --NH-O-CH₂ Ph, 112 --N(3-picolyl)CH₂ CH₂ N(CH₃)CH₂ PH, 113 --N(CH₃)CH₂ CH₂ N(CH₃)(4-methoxybenzyl), 114 --N(4-picolyl)CH₂ CH₂ N(CH₃)CH₂ Ph, 115 --N(2-picolyl)CH₂ CH₂ N(CH₃)CH₂ Ph, 116 --N(CH₃)CH₂ CH₂ N(CH₃)(2,4-dimethylbenzyl), 117 --N(CH₃)CH₂ CH₂ (2,6-dimethyl-4-morpholinyl), 118 --NH₂, 119 --NHCH₃, 120 4-morpholinyl, 121 cis-2,6-dimethyl-4-morpholinyl, 122 --NH--CH₂ CH₂ CH₂ CH₃, 123 --N(CH₃)CH₂ CH₂ N(CH₃)C(═N--CN)NHPh, 124 --N(CH₃)CH₂ CH₂ N(CH₃)(3-fluorobenzyl), 125 --N(CH₃)CH₂ CH₂ N(CH₃)(2-chlorobenzyl), 12-- N(CH₃)CH₂ CH₂ N(CH₃)(3-methoxybenzyl), 127 --N(CH₃)CH₂ CH₂ N(CH₃)(3,5-dimethoxybenzyl), 128 3,4-dihydro-6,7-dimethoxy-2-(1H)iso-quinolinyl, 129 --N(CH₃)(1-benzyl-4-piperidinyl), 130 --N(CH₃)CH₂ CH₂ N(CH₃)(2-adamantyl), 131 --N(CH₃)(4-piperidinyl), 132 5-Methyl-2,5-diazabicyclo[2.2.1 ]hept-2-yl, 133 --N(CH₃)CH₂ CO₂ H, 134 --N(CH₃)CH₂ CH₂ CH₂ N(CH₃)CH₂ CH₃, 135 --N(CH₃)(1-methyl-4-piperidinyl), 136 --N(CH₃)(1-propyl-4-piperidinyl), 137 --N(CH₃)(1-ethyl-4-piperidinyl), 138 --N(CH₃)CH₂ CH(CH₃)N(CH₃)CH₂ Ph, 139 --N(CH₃)CH₂ CH(CH₃)N(CH₃)₂, 140 --N(CH₃)CH₂ CH₂ NH(2-adamantyl), 141 --N(CH₃)CH₂ CH₂ N(CH₃)(6,6-dimethylbicyclo-[3.1 .1]hept-2-yl, 142 --NH(t-Bu), 143 --N(CH₃)CH₂ CH₂ N(CH₃)(1-cyclohexen-1-yl), 144 --N(CH₃)CH₂ CH₂ NHC(CH₃)₂ CH═CH₂, 145 2-S-carboxamido-1-pyrrolidinyl, 146 2-hydroxymethyl-1-piperidinyl, 147 3-dimethylamino-1-pyrrolidinyl, 148 --N(CH₃)CH₂ CH₂ N(CH₃)(cyclohexylmethyl), 149 --N(CH₃)CH₂ CH₂ N(CH₂ CH=CH₂)C(CH₃)₂ CH═CH₂, 150 --N(CH₃)CH₂ CH₂ N(CH₃)(4-ethylcyclohexyl), 151 --N(CH₃)CH₂ CH₂ N(CH₃)(2-ethylcyclohexyl), 152 --N(CH₃)CH₂ CH₂ N(CH₃)(4-methylcyclohexyl), 153 --N(CH₃)CH₂ CH₂ N(CH₃)(cyclohexyl), 154 --N(CH₃)CH₂ CH₂ N(CH₃)CH₂ C(O)N(CH₃)₂, 155 3-dimethylamino-1-azetidinyl, 156 1-diphenylmethyl-3-azetidinyl, 157 --N(CH)CH₂ CH₂ N(CH₃)(cyclohexylmethyl), or 158 --NH CH₂ CH₂ N(Et)CH₂ CH₂ OCH₃.
 28. A compound according to claim 10 which is(a) [S-(R*,S*)]-2-[4-[(4-morpholinyl)carbonyl]phenoxy]-3,3-diethyl-N-[1-(4-methylphenyl)butyl]-4-oxo-1-azetidinecarboxamide, or (b) [S-(R*,S*)]-2-[4-[(4-morpholinyl)carbonyl]phenoxy]3,3-diethyl-N-[1-(3,4-methylenedioxyphenyl)butyl]-4-oxo-1-azetidinecarboxamide.
 29. A compound according to claim 10 whereinRa is(1) hydrogen, (2) C₁₋₆ alkyl, (3) halo, (5) C₁₋₆ alkoxy, (6) phenyl, (7) C₁₋₆ alkylcarbonyl, (8) di-(C₁₋₆ alkyl)amino; Rb is hydrogen or C₁₋₆ alkyl, R² is(1) hydrogen, (2) C₁₋₆ alkyl, (3) halo, (5) C₁₋₆ alkoxy, (6) phenyl, (7) C₁₋₆ alkylcarbonyl, or (8) di-(C₁₋₆ alkyl)amino, R³ is(1) C₁₋₆ alkyl, (2) halo, (4) C₁₋₆ alkoxy, (5) phenyl, (6)C₁₋₆ alkylcarbonyl, (7) di-(C₁₋₆ alkyl)amino, or R² and R³ may be joined together to form a methylenedioxy group or a furan ring; R₄ is ##STR65## R₇ is (b) ethyl, propyl, butyl, pentyl or hexyl,(c) cyclopropyl, (d) C₁₋₃ alkoxy C₁₋₃ alkyl, (e) hydroxyethyl, (f) carboethoxymethyl, R₈ is(b) C₁₋₃ alkyl, (c) cyclopropyl, (d) C₁₋₃ alkoxy C₁₋₃ alkyl, (e) hydroxyethyl, (f) carboethoxymethyl, or R₇ and R₈ are joined together with the nitrogen to which they are attached to form mono or di substituted monocyclic ring which is piperidinyl or morpholinyl, said ring optionally substituted with hydrogen or methyl.
 30. A compound according to claim 10 whereinR is C₁₋₃ alkyl; R¹ is C₁₋₃ alkyl; M is(1) ethyl, propyl, butyl, pentyl or hexyl, or (2) C₂₋₆ alkenyl; R² is(a) hydrogen, (b) C₁₋₆ alkyl or C₁₋₆ alkoxy, or R³ is hydrogen, or R² and R³ are joined together to form a methylenedioxy group or a furan ring; R₉, R₁₀ and R₁₁ are each independently selected from hydrogen, C₁₋₄ alkyl, and C₁₋₃ alkoxy-C₁₋₃ alkyl; R₇ and R₈ are joined together with the nitrogen to which they are attached to form mono or di substituted ring selected from(1) piperidinyl, (2) piperazinyl, (3) morpholinyl, (4) pyrroylidinyl, (5) pyrryl, (6) imidazolyl, (7) triazolyl, (8) tetrayolyl, (9) pyrazolidinyl, or (10) azetidinyl,wherein the substituents are each selected from the group consisting of hydrogen and C₁₋₃ alkyl, benzyloxycarbonyl, phenyl C₁₋₃ alkyl amino carbonyl, pyrolidinyl, methyl, hydroxy C₁₋₃ alkyl, C₁₋₆ alkyloxy, C₁₋₄ alkyloxy carbonyl, and oxo.
 31. A compound according to claim 30 whereinR is methyl or ethyl; R¹ is methyl or ethyl; M is(1) ethyl, propyl or butyl, or (2) C₂₋₃ alkenyl; R² is(a) hydrogen (b) C₁₋₃ alkyl or C₁₋₃ alkoxy. 